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  • Models, Molecular  (100)
  • Protein Binding  (52)
  • Models, Biological
  • Nature Publishing Group (NPG)  (157)
  • American Institute of Physics (AIP)
  • Wiley
  • 2010-2014  (157)
  • 1990-1994
  • 2013  (157)
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  • 2010-2014  (157)
  • 1990-1994
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  • 1
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    A solution to release twisted DNA during chromosome replication by coupled DNA polymerases (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-03-29
    Description: Chromosomal replication machines contain coupled DNA polymerases that simultaneously replicate the leading and lagging strands. However, coupled replication presents a largely unrecognized topological problem. Because DNA polymerase must travel a helical path during synthesis, the physical connection between leading- and lagging-strand polymerases causes the daughter strands to entwine, or produces extensive build-up of negative supercoils in the newly synthesized DNA. How DNA polymerases maintain their connection during coupled replication despite these topological challenges is unknown. Here we examine the dynamics of the Escherichia coli replisome, using ensemble and single-molecule methods, and show that the replisome may solve the topological problem independent of topoisomerases. We find that the lagging-strand polymerase frequently releases from an Okazaki fragment before completion, leaving single-strand gaps behind. Dissociation of the polymerase does not result in loss from the replisome because of its contact with the leading-strand polymerase. This behaviour, referred to as 'signal release', had been thought to require a protein, possibly primase, to pry polymerase from incompletely extended DNA fragments. However, we observe that signal release is independent of primase and does not seem to require a protein trigger at all. Instead, the lagging-strand polymerase is simply less processive in the context of a replisome. Interestingly, when the lagging-strand polymerase is supplied with primed DNA in trans, uncoupling it from the fork, high processivity is restored. Hence, we propose that coupled polymerases introduce topological changes, possibly by accumulation of superhelical tension in the newly synthesized DNA, that cause lower processivity and transient lagging-strand polymerase dissociation from DNA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618558/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618558/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kurth, Isabel -- Georgescu, Roxana E -- O'Donnell, Mike E -- GM38839/GM/NIGMS NIH HHS/ -- R01 GM038839/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Apr 4;496(7443):119-22. doi: 10.1038/nature11988. Epub 2013 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Rockefeller University, Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23535600" target="_blank"〉PubMed〈/a〉
    Keywords: DNA/chemistry/genetics/metabolism ; DNA Primase/metabolism ; *DNA Replication ; DNA, Bacterial/biosynthesis/chemistry/genetics/*metabolism ; DNA, Superhelical/biosynthesis/chemistry/genetics/metabolism ; DNA-Binding Proteins/chemistry/metabolism ; DNA-Directed DNA Polymerase/chemistry/*metabolism ; Escherichia coli/*enzymology/*genetics ; Microscopy, Fluorescence ; Multienzyme Complexes/chemistry/*metabolism ; *Nucleic Acid Conformation ; Protein Binding
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  • 2
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    X-ray structure of the mammalian GIRK2-betagamma G-protein complex (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-06-07
    Description: G-protein-gated inward rectifier K(+) (GIRK) channels allow neurotransmitters, through G-protein-coupled receptor stimulation, to control cellular electrical excitability. In cardiac and neuronal cells this control regulates heart rate and neural circuit activity, respectively. Here we present the 3.5 A resolution crystal structure of the mammalian GIRK2 channel in complex with betagamma G-protein subunits, the central signalling complex that links G-protein-coupled receptor stimulation to K(+) channel activity. Short-range atomic and long-range electrostatic interactions stabilize four betagamma G-protein subunits at the interfaces between four K(+) channel subunits, inducing a pre-open state of the channel. The pre-open state exhibits a conformation that is intermediate between the closed conformation and the open conformation of the constitutively active mutant. The resultant structural picture is compatible with 'membrane delimited' activation of GIRK channels by G proteins and the characteristic burst kinetics of channel gating. The structures also permit a conceptual understanding of how the signalling lipid phosphatidylinositol-4,5-bisphosphate (PIP2) and intracellular Na(+) ions participate in multi-ligand regulation of GIRK channels.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654628/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4654628/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Whorton, Matthew R -- MacKinnon, Roderick -- 1S10RR022321-01/RR/NCRR NIH HHS/ -- 1S10RR027037-01/RR/NCRR NIH HHS/ -- S10 RR027037/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 13;498(7453):190-7. doi: 10.1038/nature12241. Epub 2013 Jun 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23739333" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; G Protein-Coupled Inwardly-Rectifying Potassium ; Channels/*chemistry/genetics/metabolism ; Heterotrimeric GTP-Binding Proteins/*chemistry/genetics/metabolism ; Humans ; Ion Channel Gating ; Models, Biological ; Models, Molecular ; Phosphatidylinositol 4,5-Diphosphate/metabolism ; Protein Conformation ; Protein Interaction Domains and Motifs ; Protein Subunits/chemistry/metabolism ; Sodium/metabolism ; Static Electricity
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Hepatitis-C-virus-like internal ribosome entry sites displace eIF3 to gain access to the 40S subunit (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-05
    Description: Hepatitis C virus (HCV) and classical swine fever virus (CSFV) messenger RNAs contain related (HCV-like) internal ribosome entry sites (IRESs) that promote 5'-end independent initiation of translation, requiring only a subset of the eukaryotic initiation factors (eIFs) needed for canonical initiation on cellular mRNAs. Initiation on HCV-like IRESs relies on their specific interaction with the 40S subunit, which places the initiation codon into the P site, where it directly base-pairs with eIF2-bound initiator methionyl transfer RNA to form a 48S initiation complex. However, all HCV-like IRESs also specifically interact with eIF3 (refs 2, 5-7, 9-12), but the role of this interaction in IRES-mediated initiation has remained unknown. During canonical initiation, eIF3 binds to the 40S subunit as a component of the 43S pre-initiation complex, and comparison of the ribosomal positions of eIF3 and the HCV IRES revealed that they overlap, so that their rearrangement would be required for formation of ribosomal complexes containing both components. Here we present a cryo-electron microscopy reconstruction of a 40S ribosomal complex containing eIF3 and the CSFV IRES. Remarkably, although the position and interactions of the CSFV IRES with the 40S subunit in this complex are similar to those of the HCV IRES in the 40S-IRES binary complex, eIF3 is completely displaced from its ribosomal position in the 43S complex, and instead interacts through its ribosome-binding surface exclusively with the apical region of domain III of the IRES. Our results suggest a role for the specific interaction of HCV-like IRESs with eIF3 in preventing ribosomal association of eIF3, which could serve two purposes: relieving the competition between the IRES and eIF3 for a common binding site on the 40S subunit, and reducing formation of 43S complexes, thereby favouring translation of viral mRNAs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106463/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4106463/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hashem, Yaser -- des Georges, Amedee -- Dhote, Vidya -- Langlois, Robert -- Liao, Hstau Y -- Grassucci, Robert A -- Pestova, Tatyana V -- Hellen, Christopher U T -- Frank, Joachim -- R01 AI51340/AI/NIAID NIH HHS/ -- R01 GM029169/GM/NIGMS NIH HHS/ -- R01 GM59660/GM/NIGMS NIH HHS/ -- R01GM29169/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 28;503(7477):539-43. doi: 10.1038/nature12658. Epub 2013 Nov 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute (HHMI), Department of Biochemistry and Molecular Biophysics, Columbia University, New York City, New York 10032, USA [2] Department of Biochemistry and Molecular Biophysics, Columbia University, New York City, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24185006" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding, Competitive ; Classical swine fever virus/*genetics ; Cryoelectron Microscopy ; Eukaryotic Initiation Factor-3/chemistry/*metabolism/ultrastructure ; Humans ; Models, Molecular ; Protein Biosynthesis ; RNA, Viral/*genetics/*metabolism ; Rabbits ; Regulatory Sequences, Ribonucleic Acid/*genetics ; Ribosome Subunits, Small, Eukaryotic/chemistry/*metabolism/ultrastructure ; Ribosomes/chemistry/*metabolism/ultrastructure
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  • 4
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    Polymerase IV occupancy at RNA-directed DNA methylation sites requires SHH1 (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-05-03
    Description: DNA methylation is an epigenetic modification that has critical roles in gene silencing, development and genome integrity. In Arabidopsis, DNA methylation is established by DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2) and targeted by 24-nucleotide small interfering RNAs (siRNAs) through a pathway termed RNA-directed DNA methylation (RdDM). This pathway requires two plant-specific RNA polymerases: Pol-IV, which functions to initiate siRNA biogenesis, and Pol-V, which functions to generate scaffold transcripts that recruit downstream RdDM factors. To understand the mechanisms controlling Pol-IV targeting we investigated the function of SAWADEE HOMEODOMAIN HOMOLOG 1 (SHH1), a Pol-IV-interacting protein. Here we show that SHH1 acts upstream in the RdDM pathway to enable siRNA production from a large subset of the most active RdDM targets, and that SHH1 is required for Pol-IV occupancy at these same loci. We also show that the SHH1 SAWADEE domain is a novel chromatin-binding module that adopts a unique tandem Tudor-like fold and functions as a dual lysine reader, probing for both unmethylated K4 and methylated K9 modifications on the histone 3 (H3) tail. Finally, we show that key residues within both lysine-binding pockets of SHH1 are required in vivo to maintain siRNA and DNA methylation levels as well as Pol-IV occupancy at RdDM targets, demonstrating a central role for methylated H3K9 binding in SHH1 function and providing the first insights into the mechanism of Pol-IV targeting. Given the parallels between methylation systems in plants and mammals, a further understanding of this early targeting step may aid our ability to control the expression of endogenous and newly introduced genes, which has broad implications for agriculture and gene therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119789/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119789/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Law, Julie A -- Du, Jiamu -- Hale, Christopher J -- Feng, Suhua -- Krajewski, Krzysztof -- Palanca, Ana Marie S -- Strahl, Brian D -- Patel, Dinshaw J -- Jacobsen, Steven E -- GM60398/GM/NIGMS NIH HHS/ -- GM85394/GM/NIGMS NIH HHS/ -- R01 GM060398/GM/NIGMS NIH HHS/ -- R37 GM060398/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 20;498(7454):385-9. doi: 10.1038/nature12178. Epub 2013 May 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular, Cell and Developmental Biology, University of California at Los Angeles, Los Angeles, California 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23636332" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*enzymology/genetics/*metabolism ; Arabidopsis Proteins/chemistry/genetics/*metabolism ; Binding Sites/genetics ; Chromatin/chemistry/genetics/metabolism ; Crystallography, X-Ray ; DNA Methylation/*genetics ; DNA-Directed RNA Polymerases/genetics/*metabolism ; Epigenesis, Genetic/genetics ; Histones/chemistry/metabolism ; Homeodomain Proteins/chemistry/*metabolism ; Lysine/chemistry/metabolism ; Methyltransferases/genetics/metabolism ; Models, Molecular ; Mutation ; Protein Folding ; Protein Structure, Tertiary ; RNA, Small Interfering/biosynthesis/genetics/metabolism
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  • 5
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    Structural basis for viral 5'-PPP-RNA recognition by human IFIT proteins (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-01-22
    Description: Interferon-induced proteins with tetratricopeptide repeats (IFITs) are innate immune effector molecules that are thought to confer antiviral defence through disruption of protein-protein interactions in the host translation-initiation machinery. However, it was recently discovered that IFITs can directly recognize viral RNA bearing a 5'-triphosphate group (PPP-RNA), which is a molecular signature that distinguishes it from host RNA. Here we report crystal structures of human IFIT5, its complex with PPP-RNAs, and an amino-terminal fragment of IFIT1. The structures reveal a new helical domain that houses a positively charged cavity designed to specifically engage only single-stranded PPP-RNA, thus distinguishing it from the canonical cytosolic sensor of double-stranded viral PPP-RNA, retinoic acid-inducible gene I (RIG-I, also known as DDX58). Mutational analysis, proteolysis and gel-shift assays reveal that PPP-RNA is bound in a non-sequence-specific manner and requires a 5'-overhang of approximately three nucleotides. Abrogation of PPP-RNA binding in IFIT1 and IFIT5 was found to cause a defect in the antiviral response by human embryonic kidney cells. These results demonstrate the mechanism by which IFIT proteins selectively recognize viral RNA, and lend insight into their downstream effector function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbas, Yazan M -- Pichlmair, Andreas -- Gorna, Maria W -- Superti-Furga, Giulio -- Nagar, Bhushan -- MOP-82929/Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Feb 7;494(7435):60-4. doi: 10.1038/nature11783. Epub 2013 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Groupe de Recherche Axe sur la Structure des Proteines, McGill University, Montreal, Quebec H3G 0B1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23334420" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Binding Sites ; Carrier Proteins/*chemistry/*metabolism ; Humans ; Immunity, Innate/immunology ; Models, Molecular ; Neoplasm Proteins/*chemistry/*metabolism ; Phosphorylation ; Protein Conformation ; RNA, Viral/*chemistry/genetics/*metabolism ; Reproducibility of Results ; Substrate Specificity
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  • 6
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    Effect of natural genetic variation on enhancer selection and function (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-10-15
    Description: The mechanisms by which genetic variation affects transcription regulation and phenotypes at the nucleotide level are incompletely understood. Here we use natural genetic variation as an in vivo mutagenesis screen to assess the genome-wide effects of sequence variation on lineage-determining and signal-specific transcription factor binding, epigenomics and transcriptional outcomes in primary macrophages from different mouse strains. We find substantial genetic evidence to support the concept that lineage-determining transcription factors define epigenetic and transcriptomic states by selecting enhancer-like regions in the genome in a collaborative fashion and facilitating binding of signal-dependent factors. This hierarchical model of transcription factor function suggests that limited sets of genomic data for lineage-determining transcription factors and informative histone modifications can be used for the prioritization of disease-associated regulatory variants.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994126/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994126/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heinz, S -- Romanoski, C E -- Benner, C -- Allison, K A -- Kaikkonen, M U -- Orozco, L D -- Glass, C K -- 5T32DK007494/DK/NIDDK NIH HHS/ -- CA17390/CA/NCI NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK091183/DK/NIDDK NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P30 CA023100/CA/NCI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R01 CA173903/CA/NCI NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- T32 AR059033/AR/NIAMS NIH HHS/ -- England -- Nature. 2013 Nov 28;503(7477):487-92. doi: 10.1038/nature12615. Epub 2013 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, Mail Code 0651, La Jolla, California 92093, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24121437" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs/genetics ; Animals ; Base Sequence ; Cell Lineage/genetics ; DNA-Binding Proteins/metabolism ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation/*genetics ; Genetic Variation/*genetics ; Histones/chemistry/metabolism ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Models, Biological ; Mutation/genetics ; NF-kappa B/metabolism ; Protein Binding ; Reproducibility of Results ; Selection, Genetic/*genetics ; Transcription Factor RelA/metabolism ; Transcription Factors/*metabolism
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  • 7
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    The sarcolipin-bound calcium pump stabilizes calcium sites exposed to the cytoplasm (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-03-05
    Description: The contraction and relaxation of muscle cells is controlled by the successive rise and fall of cytosolic Ca(2+), initiated by the release of Ca(2+) from the sarcoplasmic reticulum and terminated by re-sequestration of Ca(2+) into the sarcoplasmic reticulum as the main mechanism of Ca(2+) removal. Re-sequestration requires active transport and is catalysed by the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA), which has a key role in defining the contractile properties of skeletal and heart muscle tissue. The activity of SERCA is regulated by two small, homologous membrane proteins called phospholamban (PLB, also known as PLN) and sarcolipin (SLN). Detailed structural information explaining this regulatory mechanism has been lacking, and the structural features defining the pathway through which cytoplasmic Ca(2+) enters the intramembranous binding sites of SERCA have remained unknown. Here we report the crystal structure of rabbit SERCA1a (also known as ATP2A1) in complex with SLN at 3.1 A resolution. The regulatory SLN traps the Ca(2+)-ATPase in a previously undescribed E1 state, with exposure of the Ca(2+) sites through an open cytoplasmic pathway stabilized by Mg(2+). The structure suggests a mechanism for selective Ca(2+) loading and activation of SERCA, and provides new insight into how SLN and PLB inhibition arises from stabilization of this E1 intermediate state without bound Ca(2+). These findings may prove useful in studying how autoinhibitory domains of other ion pumps modulate transport across biological membranes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winther, Anne-Marie L -- Bublitz, Maike -- Karlsen, Jesper L -- Moller, Jesper V -- Hansen, John B -- Nissen, Poul -- Buch-Pedersen, Morten J -- England -- Nature. 2013 Mar 14;495(7440):265-9. doi: 10.1038/nature11900. Epub 2013 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Pcovery, Thorvaldsensvej 57, DK-1871 Frederiksberg, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23455424" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Calcium/*metabolism ; Calcium-Binding Proteins/chemistry/metabolism ; Crystallography, X-Ray ; Cytoplasm/*metabolism ; Enzyme Activation ; Magnesium/metabolism ; Models, Molecular ; Muscle Proteins/chemistry/*metabolism ; Phosphorylation ; Protein Binding ; Proteolipids/chemistry/*metabolism ; Rabbits ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/*chemistry/*metabolism
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  • 8
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    The structure of the box C/D enzyme reveals regulation of RNA methylation (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-10-15
    Description: Post-transcriptional modifications are essential to the cell life cycle, as they affect both pre-ribosomal RNA processing and ribosome assembly. The box C/D ribonucleoprotein enzyme that methylates ribosomal RNA at the 2'-O-ribose uses a multitude of guide RNAs as templates for the recognition of rRNA target sites. Two methylation guide sequences are combined on each guide RNA, the significance of which has remained unclear. Here we use a powerful combination of NMR spectroscopy and small-angle neutron scattering to solve the structure of the 390 kDa archaeal RNP enzyme bound to substrate RNA. We show that the two methylation guide sequences are located in different environments in the complex and that the methylation of physiological substrates targeted by the same guide RNA occurs sequentially. This structure provides a means for differential control of methylation levels at the two sites and at the same time offers an unexpected regulatory mechanism for rRNA folding.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lapinaite, Audrone -- Simon, Bernd -- Skjaerven, Lars -- Rakwalska-Bange, Magdalena -- Gabel, Frank -- Carlomagno, Teresa -- England -- Nature. 2013 Oct 24;502(7472):519-23. doi: 10.1038/nature12581. Epub 2013 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, Structural and Computational Biology Unit, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24121435" target="_blank"〉PubMed〈/a〉
    Keywords: Apoproteins/chemistry/metabolism ; Archaeal Proteins/chemistry/metabolism ; Biocatalysis ; Chromosomal Proteins, Non-Histone/metabolism ; Methylation ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; Nucleic Acid Conformation ; Pyrococcus furiosus/*enzymology/*genetics ; RNA Folding ; *RNA Processing, Post-Transcriptional ; RNA, Archaeal/chemistry/genetics/metabolism ; RNA, Guide/chemistry/genetics/metabolism ; RNA, Ribosomal/*chemistry/*metabolism ; Ribonucleoproteins, Small Nucleolar/*chemistry/*metabolism
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  • 9
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    cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger that activates STING (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-06-01
    Description: Detection of cytoplasmic DNA represents one of the most fundamental mechanisms of the innate immune system to sense the presence of microbial pathogens. Moreover, erroneous detection of endogenous DNA by the same sensing mechanisms has an important pathophysiological role in certain sterile inflammatory conditions. The endoplasmic-reticulum-resident protein STING is critically required for the initiation of type I interferon signalling upon detection of cytosolic DNA of both exogenous and endogenous origin. Next to its pivotal role in DNA sensing, STING also serves as a direct receptor for the detection of cyclic dinucleotides, which function as second messenger molecules in bacteria. DNA recognition, however, is triggered in an indirect fashion that depends on a recently characterized cytoplasmic nucleotidyl transferase, termed cGAMP synthase (cGAS), which upon interaction with DNA synthesizes a dinucleotide molecule that in turn binds to and activates STING. We here show in vivo and in vitro that the cGAS-catalysed reaction product is distinct from previously characterized cyclic dinucleotides. Using a combinatorial approach based on mass spectrometry, enzymatic digestion, NMR analysis and chemical synthesis we demonstrate that cGAS produces a cyclic GMP-AMP dinucleotide, which comprises a 2'-5' and a 3'-5' phosphodiester linkage 〉Gp(2'-5')Ap(3'-5')〉. We found that the presence of this 2'-5' linkage was required to exert potent activation of human STING. Moreover, we show that cGAS first catalyses the synthesis of a linear 2'-5'-linked dinucleotide, which is then subject to cGAS-dependent cyclization in a second step through a 3'-5' phosphodiester linkage. This 13-membered ring structure defines a novel class of second messenger molecules, extending the family of 2'-5'-linked antiviral biomolecules.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143541/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143541/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ablasser, Andrea -- Goldeck, Marion -- Cavlar, Taner -- Deimling, Tobias -- Witte, Gregor -- Rohl, Ingo -- Hopfner, Karl-Peter -- Ludwig, Janos -- Hornung, Veit -- 243046/European Research Council/International -- U19AI083025/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jun 20;498(7454):380-4. doi: 10.1038/nature12306. Epub 2013 May 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, 53127 Bonn, Germany. andrea.ablasser@uni-bonn.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23722158" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Monophosphate/chemistry ; Animals ; Biocatalysis ; Cell Line ; Cyclic GMP/chemistry ; Cyclization ; HEK293 Cells ; Humans ; Magnetic Resonance Spectroscopy ; Membrane Proteins/*metabolism ; Mice ; Models, Molecular ; Molecular Structure ; Nucleotidyltransferases/genetics/*metabolism ; Oligoribonucleotides/biosynthesis/chemistry/*metabolism ; Second Messenger Systems/*physiology
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    Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs (2013)
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    Publication Date: 2013-10-15
    Description: The design of G-protein-coupled receptor (GPCR) allosteric modulators, an active area of modern pharmaceutical research, has proved challenging because neither the binding modes nor the molecular mechanisms of such drugs are known. Here we determine binding sites, bound conformations and specific drug-receptor interactions for several allosteric modulators of the M2 muscarinic acetylcholine receptor (M2 receptor), a prototypical family A GPCR, using atomic-level simulations in which the modulators spontaneously associate with the receptor. Despite substantial structural diversity, all modulators form cation-pi interactions with clusters of aromatic residues in the receptor extracellular vestibule, approximately 15 A from the classical, 'orthosteric' ligand-binding site. We validate the observed modulator binding modes through radioligand binding experiments on receptor mutants designed, on the basis of our simulations, either to increase or to decrease modulator affinity. Simulations also revealed mechanisms that contribute to positive and negative allosteric modulation of classical ligand binding, including coupled conformational changes of the two binding sites and electrostatic interactions between ligands in these sites. These observations enabled the design of chemical modifications that substantially alter a modulator's allosteric effects. Our findings thus provide a structural basis for the rational design of allosteric modulators targeting muscarinic and possibly other GPCRs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dror, Ron O -- Green, Hillary F -- Valant, Celine -- Borhani, David W -- Valcourt, James R -- Pan, Albert C -- Arlow, Daniel H -- Canals, Meritxell -- Lane, J Robert -- Rahmani, Raphael -- Baell, Jonathan B -- Sexton, Patrick M -- Christopoulos, Arthur -- Shaw, David E -- England -- Nature. 2013 Nov 14;503(7475):295-9. doi: 10.1038/nature12595. Epub 2013 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] D. E. Shaw Research, 120 West 45th Street, 39th Floor, New York, New York 10036, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24121438" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/physiology ; Animals ; Binding Sites ; CHO Cells ; Cricetulus ; *Drug Design ; Humans ; Models, Chemical ; Molecular Conformation ; Molecular Dynamics Simulation ; Mutation ; Protein Binding ; Receptors, G-Protein-Coupled/*antagonists & inhibitors/*chemistry/genetics ; Reproducibility of Results
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    Structural basis for the drug extrusion mechanism by a MATE multidrug transporter (2013)
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    Publication Date: 2013-03-29
    Description: Multidrug and toxic compound extrusion (MATE) family transporters are conserved in the three primary domains of life (Archaea, Bacteria and Eukarya), and export xenobiotics using an electrochemical gradient of H(+) or Na(+) across the membrane. MATE transporters confer multidrug resistance to bacterial pathogens and cancer cells, thus causing critical reductions in the therapeutic efficacies of antibiotics and anti-cancer drugs, respectively. Therefore, the development of MATE inhibitors has long been awaited in the field of clinical medicine. Here we present the crystal structures of the H(+)-driven MATE transporter from Pyrococcus furiosus in two distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides, at 2.1-3.0 A resolutions. The structures, combined with functional analyses, show that the protonation of Asp 41 on the amino (N)-terminal lobe induces the bending of TM1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extracellular space. Moreover, the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities. The strongest inhibitory peptide that occupies the N-lobe cavity may pave the way towards the development of efficient inhibitors against MATE transporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tanaka, Yoshiki -- Hipolito, Christopher J -- Maturana, Andres D -- Ito, Koichi -- Kuroda, Teruo -- Higuchi, Takashi -- Katoh, Takayuki -- Kato, Hideaki E -- Hattori, Motoyuki -- Kumazaki, Kaoru -- Tsukazaki, Tomoya -- Ishitani, Ryuichiro -- Suga, Hiroaki -- Nureki, Osamu -- England -- Nature. 2013 Apr 11;496(7444):247-51. doi: 10.1038/nature12014. Epub 2013 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉RIKEN Advanced Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23535598" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Antiporters/*chemistry/*metabolism ; Apoproteins/chemistry/metabolism ; Archaeal Proteins/*chemistry/*metabolism ; Aspartic Acid/chemistry ; Crystallography, X-Ray ; DNA Mutational Analysis ; Macrocyclic Compounds/chemistry/metabolism ; Models, Molecular ; Molecular Sequence Data ; Norfloxacin/chemistry/metabolism ; Peptides/chemistry/metabolism ; Protein Conformation ; Protons ; Pyrococcus furiosus/*chemistry ; Structure-Activity Relationship ; Sulfides/chemistry/metabolism
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    Structure of class B GPCR corticotropin-releasing factor receptor 1 (2013)
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    Publication Date: 2013-07-19
    Description: Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-releasing factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-releasing factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hollenstein, Kaspar -- Kean, James -- Bortolato, Andrea -- Cheng, Robert K Y -- Dore, Andrew S -- Jazayeri, Ali -- Cooke, Robert M -- Weir, Malcolm -- Marshall, Fiona H -- England -- Nature. 2013 Jul 25;499(7459):438-43. doi: 10.1038/nature12357. Epub 2013 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Heptares Therapeutics Ltd, BioPark, Broadwater Road, Welwyn Garden City AL7 3AX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23863939" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Aminopyridines/chemistry/metabolism/pharmacology ; Binding Sites ; Conserved Sequence ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Structure, Tertiary ; Receptors, Corticotropin-Releasing Hormone/antagonists & ; inhibitors/*chemistry/*classification/metabolism ; Receptors, Dopamine D3/antagonists & inhibitors/chemistry/classification
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    Unusual base pairing during the decoding of a stop codon by the ribosome (2013)
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    Publication Date: 2013-07-03
    Description: During normal translation, the binding of a release factor to one of the three stop codons (UGA, UAA or UAG) results in the termination of protein synthesis. However, modification of the initial uridine to a pseudouridine (Psi) allows efficient recognition and read-through of these stop codons by a transfer RNA (tRNA), although it requires the formation of two normally forbidden purine-purine base pairs. Here we determined the crystal structure at 3.1 A resolution of the 30S ribosomal subunit in complex with the anticodon stem loop of tRNA(Ser) bound to the PsiAG stop codon in the A site. The PsiA base pair at the first position is accompanied by the formation of purine-purine base pairs at the second and third positions of the codon, which show an unusual Watson-Crick/Hoogsteen geometry. The structure shows a previously unsuspected ability of the ribosomal decoding centre to accommodate non-canonical base pairs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732562/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732562/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fernandez, Israel S -- Ng, Chyan Leong -- Kelley, Ann C -- Wu, Guowei -- Yu, Yi-Tao -- Ramakrishnan, V -- 096570/Wellcome Trust/United Kingdom -- GM104077/GM/NIGMS NIH HHS/ -- MC_U105184332/Medical Research Council/United Kingdom -- R01 GM104077/GM/NIGMS NIH HHS/ -- R21 AG039559/AG/NIA NIH HHS/ -- U105184332/Medical Research Council/United Kingdom -- England -- Nature. 2013 Aug 1;500(7460):107-10. doi: 10.1038/nature12302. Epub 2013 Jun 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23812587" target="_blank"〉PubMed〈/a〉
    Keywords: Anticodon/chemistry/genetics/metabolism ; *Base Pairing ; Base Sequence ; Codon, Terminator/chemistry/*genetics/*metabolism ; Crystallography, X-Ray ; Models, Molecular ; Nucleic Acid Conformation ; Protein Conformation ; Pseudouridine/chemistry/genetics/metabolism ; RNA, Transfer, Ser/chemistry/genetics/metabolism ; Ribosome Subunits, Small, Bacterial/chemistry/genetics/metabolism ; Ribosomes/*chemistry/genetics/*metabolism
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    Crystal structure of the integral membrane diacylglycerol kinase (2013)
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    Publication Date: 2013-05-17
    Description: Diacylglycerol kinase catalyses the ATP-dependent phosphorylation of diacylglycerol to phosphatidic acid for use in shuttling water-soluble components to membrane-derived oligosaccharide and lipopolysaccharide in the cell envelope of Gram-negative bacteria. For half a century, this 121-residue kinase has served as a model for investigating membrane protein enzymology, folding, assembly and stability. Here we present crystal structures for three functional forms of this unique and paradigmatic kinase, one of which is wild type. These reveal a homo-trimeric enzyme with three transmembrane helices and an amino-terminal amphiphilic helix per monomer. Bound lipid substrate and docked ATP identify the putative active site that is of the composite, shared site type. The crystal structures rationalize extensive biochemical and biophysical data on the enzyme. They are, however, at variance with a published solution NMR model in that domain swapping, a key feature of the solution form, is not observed in the crystal structures.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740270/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740270/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Dianfan -- Lyons, Joseph A -- Pye, Valerie E -- Vogeley, Lutz -- Aragao, David -- Kenyon, Colin P -- Shah, Syed T A -- Doherty, Christine -- Aherne, Margaret -- Caffrey, Martin -- GM75915/GM/NIGMS NIH HHS/ -- P41 RR015301/RR/NCRR NIH HHS/ -- P50GM073210/GM/NIGMS NIH HHS/ -- U54 GM094599/GM/NIGMS NIH HHS/ -- U54 GM094625/GM/NIGMS NIH HHS/ -- U54GM094599/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 May 23;497(7450):521-4. doi: 10.1038/nature12179. Epub 2013 May 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biochemistry and Immunology & School of Medicine, Trinity College Dublin, Dublin 2, Ireland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23676677" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Bacterial Proteins/*chemistry/genetics/metabolism ; Catalytic Domain ; Cell Membrane/*metabolism ; Crystallography, X-Ray ; Diacylglycerol Kinase/*chemistry/genetics/*metabolism ; Enzyme Activation/drug effects ; Enzyme Stability ; Lipids ; Magnesium/metabolism ; Membrane Proteins/*chemistry/genetics/metabolism ; Models, Molecular ; Mutant Proteins/chemistry/genetics/metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Protein Conformation ; Zinc/pharmacology
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    Structural insight into the biogenesis of beta-barrel membrane proteins (2013)
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    Publication Date: 2013-09-03
    Description: beta-barrel membrane proteins are essential for nutrient import, signalling, motility and survival. In Gram-negative bacteria, the beta-barrel assembly machinery (BAM) complex is responsible for the biogenesis of beta-barrel membrane proteins, with homologous complexes found in mitochondria and chloroplasts. Here we describe the structure of BamA, the central and essential component of the BAM complex, from two species of bacteria: Neisseria gonorrhoeae and Haemophilus ducreyi. BamA consists of a large periplasmic domain attached to a 16-strand transmembrane beta-barrel domain. Three structural features shed light on the mechanism by which BamA catalyses beta-barrel assembly. First, the interior cavity is accessible in one BamA structure and conformationally closed in the other. Second, an exterior rim of the beta-barrel has a distinctly narrowed hydrophobic surface, locally destabilizing the outer membrane. And third, the beta-barrel can undergo lateral opening, suggesting a route from the interior cavity in BamA into the outer membrane.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779476/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779476/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Noinaj, Nicholas -- Kuszak, Adam J -- Gumbart, James C -- Lukacik, Petra -- Chang, Hoshing -- Easley, Nicole C -- Lithgow, Trevor -- Buchanan, Susan K -- K22 AI100927/AI/NIAID NIH HHS/ -- K22-AI100927/AI/NIAID NIH HHS/ -- R01 GM067887/GM/NIGMS NIH HHS/ -- R01-GM67887/GM/NIGMS NIH HHS/ -- RC2GM093307/GM/NIGMS NIH HHS/ -- Z99 DK999999/Intramural NIH HHS/ -- ZIA DK036139-06/Intramural NIH HHS/ -- England -- Nature. 2013 Sep 19;501(7467):385-90. doi: 10.1038/nature12521. Epub 2013 Sep 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23995689" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Outer Membrane Proteins/*biosynthesis/*chemistry/genetics ; Cell Membrane/chemistry/metabolism ; Crystallography, X-Ray ; Escherichia coli/chemistry/genetics ; Escherichia coli Proteins/chemistry/genetics ; Haemophilus/*chemistry ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Mutagenesis ; Neisseria gonorrhoeae/*chemistry ; Protein Conformation ; Structural Homology, Protein
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    Crystal structure of the 14-subunit RNA polymerase I (2013)
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    Publication Date: 2013-10-25
    Description: Protein biosynthesis depends on the availability of ribosomes, which in turn relies on ribosomal RNA production. In eukaryotes, this process is carried out by RNA polymerase I (Pol I), a 14-subunit enzyme, the activity of which is a major determinant of cell growth. Here we present the crystal structure of Pol I from Saccharomyces cerevisiae at 3.0 A resolution. The Pol I structure shows a compact core with a wide DNA-binding cleft and a tightly anchored stalk. An extended loop mimics the DNA backbone in the cleft and may be involved in regulating Pol I transcription. Subunit A12.2 extends from the A190 jaw to the active site and inserts a transcription elongation factor TFIIS-like zinc ribbon into the nucleotide triphosphate entry pore, providing insight into the role of A12.2 in RNA cleavage and Pol I insensitivity to alpha-amanitin. The A49-A34.5 heterodimer embraces subunit A135 through extended arms, thereby contacting and potentially regulating subunit A12.2.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fernandez-Tornero, Carlos -- Moreno-Morcillo, Maria -- Rashid, Umar J -- Taylor, Nicholas M I -- Ruiz, Federico M -- Gruene, Tim -- Legrand, Pierre -- Steuerwald, Ulrich -- Muller, Christoph W -- England -- Nature. 2013 Oct 31;502(7473):644-9. doi: 10.1038/nature12636. Epub 2013 Oct 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Ramiro de Maeztu 9, 28040 Madrid, Spain [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24153184" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; Models, Molecular ; Peptide Chain Elongation, Translational ; Protein Binding ; Protein Conformation ; Protein Multimerization ; Protein Subunits/*chemistry ; RNA Polymerase I/*chemistry ; RNA Polymerase II/chemistry ; RNA Polymerase III/chemistry ; Saccharomyces cerevisiae/*enzymology ; Transcription, Genetic
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    Structural basis of histone H2A-H2B recognition by the essential chaperone FACT (2013)
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    Publication Date: 2013-05-24
    Description: Facilitates chromatin transcription (FACT) is a conserved histone chaperone that reorganizes nucleosomes and ensures chromatin integrity during DNA transcription, replication and repair. Key to the broad functions of FACT is its recognition of histones H2A-H2B (ref. 2). However, the structural basis for how histones H2A-H2B are recognized and how this integrates with the other functions of FACT, including the recognition of histones H3-H4 and other nuclear factors, is unknown. Here we reveal the crystal structure of the evolutionarily conserved FACT chaperone domain Spt16M from Chaetomium thermophilum, in complex with the H2A-H2B heterodimer. A novel 'U-turn' motif scaffolded onto a Rtt106-like module embraces the alpha1 helix of H2B. Biochemical and in vivo assays validate the structure and dissect the contribution of histone tails and H3-H4 towards Spt16M binding. Furthermore, we report the structure of the FACT heterodimerization domain that connects FACT to replicative polymerases. Our results show that Spt16M makes several interactions with histones, which we suggest allow the module to invade the nucleosome gradually and block the strongest interaction of H2B with DNA. FACT would thus enhance 'nucleosome breathing' by re-organizing the first 30 base pairs of nucleosomal histone-DNA contacts. Our snapshot of the engagement of the chaperone with H2A-H2B and the structures of all globular FACT domains enable the high-resolution analysis of the vital chaperoning functions of FACT, shedding light on how the complex promotes the activity of enzymes that require nucleosome reorganization.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hondele, Maria -- Stuwe, Tobias -- Hassler, Markus -- Halbach, Felix -- Bowman, Andrew -- Zhang, Elisa T -- Nijmeijer, Bianca -- Kotthoff, Christiane -- Rybin, Vladimir -- Amlacher, Stefan -- Hurt, Ed -- Ladurner, Andreas G -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jul 4;499(7456):111-4. doi: 10.1038/nature12242. Epub 2013 May 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiological Chemistry, Butenandt Institute and LMU Biomedical Center, Faculty of Medicine, Ludwig Maximilians University of Munich, Butenandtstrasse 5, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23698368" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Chaetomium/*chemistry ; Conserved Sequence ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA Replication ; Fungal Proteins/*chemistry/*metabolism ; Histones/chemistry/*metabolism ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Molecular Chaperones/*chemistry/*metabolism ; Nucleosomes/chemistry/metabolism ; Protein Binding ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Substrate Specificity
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    Genomic evidence for ameiotic evolution in the bdelloid rotifer Adineta vaga (2013)
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    Publication Date: 2013-07-23
    Description: Loss of sexual reproduction is considered an evolutionary dead end for metazoans, but bdelloid rotifers challenge this view as they appear to have persisted asexually for millions of years. Neither male sex organs nor meiosis have ever been observed in these microscopic animals: oocytes are formed through mitotic divisions, with no reduction of chromosome number and no indication of chromosome pairing. However, current evidence does not exclude that they may engage in sex on rare, cryptic occasions. Here we report the genome of a bdelloid rotifer, Adineta vaga (Davis, 1873), and show that its structure is incompatible with conventional meiosis. At gene scale, the genome of A. vaga is tetraploid and comprises both anciently duplicated segments and less divergent allelic regions. However, in contrast to sexual species, the allelic regions are rearranged and sometimes even found on the same chromosome. Such structure does not allow meiotic pairing; instead, we find abundant evidence of gene conversion, which may limit the accumulation of deleterious mutations in the absence of meiosis. Gene families involved in resistance to oxidation, carbohydrate metabolism and defence against transposons are significantly expanded, which may explain why transposable elements cover only 3% of the assembled sequence. Furthermore, 8% of the genes are likely to be of non-metazoan origin and were probably acquired horizontally. This apparent convergence between bdelloids and prokaryotes sheds new light on the evolutionary significance of sex.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Flot, Jean-Francois -- Hespeels, Boris -- Li, Xiang -- Noel, Benjamin -- Arkhipova, Irina -- Danchin, Etienne G J -- Hejnol, Andreas -- Henrissat, Bernard -- Koszul, Romain -- Aury, Jean-Marc -- Barbe, Valerie -- Barthelemy, Roxane-Marie -- Bast, Jens -- Bazykin, Georgii A -- Chabrol, Olivier -- Couloux, Arnaud -- Da Rocha, Martine -- Da Silva, Corinne -- Gladyshev, Eugene -- Gouret, Philippe -- Hallatschek, Oskar -- Hecox-Lea, Bette -- Labadie, Karine -- Lejeune, Benjamin -- Piskurek, Oliver -- Poulain, Julie -- Rodriguez, Fernando -- Ryan, Joseph F -- Vakhrusheva, Olga A -- Wajnberg, Eric -- Wirth, Benedicte -- Yushenova, Irina -- Kellis, Manolis -- Kondrashov, Alexey S -- Mark Welch, David B -- Pontarotti, Pierre -- Weissenbach, Jean -- Wincker, Patrick -- Jaillon, Olivier -- Van Doninck, Karine -- England -- Nature. 2013 Aug 22;500(7463):453-7. doi: 10.1038/nature12326. Epub 2013 Jul 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Namur, Department of Biology, URBE, Laboratory of Evolutionary Genetics and Ecology, 5000 Namur, Belgium. jean-francois.flot@ds.mpg.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23873043" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Gene Conversion/*genetics ; Gene Transfer, Horizontal/genetics ; Genome/*genetics ; Genomics ; Meiosis/genetics ; Models, Biological ; Reproduction, Asexual/*genetics ; Rotifera/*genetics ; Tetraploidy
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Co-crystal structure of a T-box riboswitch stem I domain in complex with its cognate tRNA (2013)
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    Publication Date: 2013-07-31
    Description: In Gram-positive bacteria, T-box riboswitches regulate the expression of aminoacyl-tRNA synthetases and other proteins in response to fluctuating transfer RNA aminoacylation levels under various nutritional states. T-boxes reside in the 5'-untranslated regions of the messenger RNAs they regulate, and consist of two conserved domains. Stem I contains the specifier trinucleotide that base pairs with the anticodon of cognate tRNA. 3' to stem I is the antiterminator domain, which base pairs with the tRNA acceptor end and evaluates its aminoacylation state. Despite high phylogenetic conservation and widespread occurrence in pathogens, the structural basis of tRNA recognition by this riboswitch remains ill defined. Here we demonstrate that the ~100-nucleotide T-box stem I is necessary and sufficient for specific, high-affinity (dissociation constant (Kd) ~150 nM) tRNA binding, and report the structure of Oceanobacillus iheyensis glyQ stem I in complex with its cognate tRNA at 3.2 A resolution. Stem I recognizes the overall architecture of tRNA in addition to its anticodon, something accomplished by large ribonucleoproteins such as the ribosome, or proteins such as aminoacyl-tRNA synthetases, but is unprecedented for a compact mRNA domain. The C-shaped stem I cradles the L-shaped tRNA, forming an extended (1,604 A(2)) intermolecular interface. In addition to the specifier-anticodon interaction, two interdigitated T-loops near the apex of stem I stack on the tRNA elbow in a manner analogous to those of the J11/12-J12/11 motif of RNase P and the L1 stalk of the ribosomal E-site. Because these ribonucleoproteins and T-boxes are unrelated, this strategy to recognize a universal tRNA feature probably evolved convergently. Mutually induced fit of stem I and the tRNA exploiting the intrinsic flexibility of tRNA and its conserved post-transcriptional modifications results in high shape complementarity, which in addition to providing specificity and affinity, globally organizes the T-box to orchestrate tRNA-dependent transcription regulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808885/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3808885/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jinwei -- Ferre-D'Amare, Adrian R -- Z99 HL999999/Intramural NIH HHS/ -- ZIA HL006102-02/Intramural NIH HHS/ -- ZIA HL006150-01/Intramural NIH HHS/ -- England -- Nature. 2013 Aug 15;500(7462):363-6. doi: 10.1038/nature12440. Epub 2013 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Heart, Lung and Blood Institute, 50 South Drive, MSC 8012, Bethesda, Maryland 20892-8012, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23892783" target="_blank"〉PubMed〈/a〉
    Keywords: Bacillaceae/*chemistry ; Bacterial Proteins/*chemistry ; *Models, Molecular ; Protein Binding ; Protein Structure, Quaternary ; RNA, Transfer/*chemistry ; *Riboswitch ; T-Box Domain Proteins/*chemistry
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    Antidiabetic effects of glucokinase regulatory protein small-molecule disruptors (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-15
    Description: Glucose homeostasis is a vital and complex process, and its disruption can cause hyperglycaemia and type II diabetes mellitus. Glucokinase (GK), a key enzyme that regulates glucose homeostasis, converts glucose to glucose-6-phosphate in pancreatic beta-cells, liver hepatocytes, specific hypothalamic neurons, and gut enterocytes. In hepatocytes, GK regulates glucose uptake and glycogen synthesis, suppresses glucose production, and is subject to the endogenous inhibitor GK regulatory protein (GKRP). During fasting, GKRP binds, inactivates and sequesters GK in the nucleus, which removes GK from the gluconeogenic process and prevents a futile cycle of glucose phosphorylation. Compounds that directly hyperactivate GK (GK activators) lower blood glucose levels and are being evaluated clinically as potential therapeutics for the treatment of type II diabetes mellitus. However, initial reports indicate that an increased risk of hypoglycaemia is associated with some GK activators. To mitigate the risk of hypoglycaemia, we sought to increase GK activity by blocking GKRP. Here we describe the identification of two potent small-molecule GK-GKRP disruptors (AMG-1694 and AMG-3969) that normalized blood glucose levels in several rodent models of diabetes. These compounds potently reversed the inhibitory effect of GKRP on GK activity and promoted GK translocation both in vitro (isolated hepatocytes) and in vivo (liver). A co-crystal structure of full-length human GKRP in complex with AMG-1694 revealed a previously unknown binding pocket in GKRP distinct from that of the phosphofructose-binding site. Furthermore, with AMG-1694 and AMG-3969 (but not GK activators), blood glucose lowering was restricted to diabetic and not normoglycaemic animals. These findings exploit a new cellular mechanism for lowering blood glucose levels with reduced potential for hypoglycaemic risk in patients with type II diabetes mellitus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lloyd, David J -- St Jean, David J Jr -- Kurzeja, Robert J M -- Wahl, Robert C -- Michelsen, Klaus -- Cupples, Rod -- Chen, Michelle -- Wu, John -- Sivits, Glenn -- Helmering, Joan -- Komorowski, Renee -- Ashton, Kate S -- Pennington, Lewis D -- Fotsch, Christopher -- Vazir, Mukta -- Chen, Kui -- Chmait, Samer -- Zhang, Jiandong -- Liu, Longbin -- Norman, Mark H -- Andrews, Kristin L -- Bartberger, Michael D -- Van, Gwyneth -- Galbreath, Elizabeth J -- Vonderfecht, Steven L -- Wang, Minghan -- Jordan, Steven R -- Veniant, Murielle M -- Hale, Clarence -- England -- Nature. 2013 Dec 19;504(7480):437-40. doi: 10.1038/nature12724. Epub 2013 Nov 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ; Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. ; Department of Comparative Biology & Safety Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24226772" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Animals ; Blood Glucose/metabolism ; Carrier Proteins/*antagonists & inhibitors/metabolism ; Cell Nucleus/enzymology ; Crystallography, X-Ray ; Diabetes Mellitus, Type 2/blood/*drug therapy/enzymology ; Disease Models, Animal ; Hepatocytes ; Humans ; Hyperglycemia/blood/drug therapy/enzymology ; Hypoglycemic Agents/chemistry/*pharmacology/*therapeutic use ; Liver/cytology/enzymology/metabolism ; Male ; Models, Molecular ; Organ Specificity ; Phosphorylation/drug effects ; Piperazines/chemistry/metabolism/pharmacology/therapeutic use ; Protein Binding/drug effects ; Protein Transport/drug effects ; Rats ; Rats, Wistar ; Sulfonamides/chemistry/metabolism/pharmacology/therapeutic use
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    RNA catalyses nuclear pre-mRNA splicing (2013)
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    Publication Date: 2013-11-08
    Description: In nuclear pre-messenger RNA splicing, introns are excised by the spliceosome, a dynamic machine composed of both proteins and small nuclear RNAs (snRNAs). Over thirty years ago, after the discovery of self-splicing group II intron RNAs, the snRNAs were proposed to catalyse splicing. However, no definitive evidence for a role of either RNA or protein in catalysis by the spliceosome has been reported so far. By using metal rescue strategies in spliceosomes from budding yeast, here we show that the U6 snRNA catalyses both of the two splicing reactions by positioning divalent metals that stabilize the leaving groups during each reaction. Notably, all of the U6 catalytic metal ligands we identified correspond to the ligands observed to position catalytic, divalent metals in crystal structures of a group II intron RNA. These findings indicate that group II introns and the spliceosome share common catalytic mechanisms and probably common evolutionary origins. Our results demonstrate that RNA mediates catalysis within the spliceosome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666680/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666680/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fica, Sebastian M -- Tuttle, Nicole -- Novak, Thaddeus -- Li, Nan-Sheng -- Lu, Jun -- Koodathingal, Prakash -- Dai, Qing -- Staley, Jonathan P -- Piccirilli, Joseph A -- 5T32GM008720/GM/NIGMS NIH HHS/ -- R01 GM088656/GM/NIGMS NIH HHS/ -- R01GM088656/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Nov 14;503(7475):229-34. doi: 10.1038/nature12734. Epub 2013 Nov 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Graduate Program in Cell and Molecular Biology, The University of Chicago, Chicago, Illinois 60637, USA [2] Department of Molecular Genetics and Cell Biology, Cummings Life Sciences Center, 920 East 58th Street, The University of Chicago, Chicago, Illinois 60637, USA [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24196718" target="_blank"〉PubMed〈/a〉
    Keywords: Catalysis ; Cell Nucleus/metabolism ; Introns/genetics ; Metals/metabolism ; Models, Biological ; RNA Precursors/*metabolism ; *RNA Splicing ; RNA, Fungal/metabolism ; RNA, Small Nuclear/*metabolism ; Saccharomyces cerevisiae/*genetics/*metabolism ; Spliceosomes/metabolism
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    SCF(FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket (2013)
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    Publication Date: 2013-03-19
    Description: The cryptochrome (CRY) flavoproteins act as blue-light receptors in plants and insects, but perform light-independent functions at the core of the mammalian circadian clock. To drive clock oscillations, mammalian CRYs associate with the Period proteins (PERs) and together inhibit the transcription of their own genes. The SCF(FBXL3) ubiquitin ligase complex controls this negative feedback loop by promoting CRY ubiquitination and degradation. However, the molecular mechanisms of their interactions and the functional role of flavin adenine dinucleotide (FAD) binding in CRYs remain poorly understood. Here we report crystal structures of mammalian CRY2 in its apo, FAD-bound and FBXL3-SKP1-complexed forms. Distinct from other cryptochromes of known structures, mammalian CRY2 binds FAD dynamically with an open cofactor pocket. Notably, the F-box protein FBXL3 captures CRY2 by simultaneously occupying its FAD-binding pocket with a conserved carboxy-terminal tail and burying its PER-binding interface. This novel F-box-protein-substrate bipartite interaction is susceptible to disruption by both FAD and PERs, suggesting a new avenue for pharmacological targeting of the complex and a multifaceted regulatory mechanism of CRY ubiquitination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618506/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618506/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xing, Weiman -- Busino, Luca -- Hinds, Thomas R -- Marionni, Samuel T -- Saifee, Nabiha H -- Bush, Matthew F -- Pagano, Michele -- Zheng, Ning -- 5T32-HL007151/HL/NHLBI NIH HHS/ -- K99 CA166181/CA/NCI NIH HHS/ -- R01 GM057587/GM/NIGMS NIH HHS/ -- R01-CA107134/CA/NCI NIH HHS/ -- R01-GM057587/GM/NIGMS NIH HHS/ -- R21-CA161108/CA/NCI NIH HHS/ -- R37 CA076584/CA/NCI NIH HHS/ -- R37-CA-076584/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Apr 4;496(7443):64-8. doi: 10.1038/nature11964. Epub 2013 Mar 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23503662" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoproteins/chemistry/metabolism ; Binding Sites ; Cryptochromes/chemistry/*metabolism ; Crystallography, X-Ray ; Deoxyribodipyrimidine Photo-Lyase/chemistry ; Drosophila melanogaster/chemistry ; F-Box Proteins/chemistry/*metabolism ; Flavin-Adenine Dinucleotide/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Mice ; Models, Molecular ; Protein Structure, Tertiary ; S-Phase Kinase-Associated Proteins/chemistry/metabolism ; SKP Cullin F-Box Protein Ligases/chemistry/*metabolism ; Substrate Specificity
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    Receptor binding by a ferret-transmissible H5 avian influenza virus (2013)
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    Publication Date: 2013-04-26
    Description: Cell-surface-receptor binding by influenza viruses is a key determinant of their transmissibility, both from avian and animal species to humans as well as from human to human. Highly pathogenic avian H5N1 viruses that are a threat to public health have been observed to acquire affinity for human receptors, and transmissible-mutant-selection experiments have identified a virus that is transmissible in ferrets, the generally accepted experimental model for influenza in humans. Here, our quantitative biophysical measurements of the receptor-binding properties of haemagglutinin (HA) from the transmissible mutant indicate a small increase in affinity for human receptor and a marked decrease in affinity for avian receptor. From analysis of virus and HA binding data we have derived an algorithm that predicts virus avidity from the affinity of individual HA-receptor interactions. It reveals that the transmissible-mutant virus has a 200-fold preference for binding human over avian receptors. The crystal structure of the transmissible-mutant HA in complex with receptor analogues shows that it has acquired the ability to bind human receptor in the same folded-back conformation as seen for HA from the 1918, 1957 (ref. 4), 1968 (ref. 5) and 2009 (ref. 6) pandemic viruses. This binding mode is substantially different from that by which non-transmissible wild-type H5 virus HA binds human receptor. The structure of the complex also explains how the change in preference from avian to human receptors arises from the Gln226Leu substitution, which facilitates binding to human receptor but restricts binding to avian receptor. Both features probably contribute to the acquisition of transmissibility by this mutant virus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xiong, Xiaoli -- Coombs, Peter J -- Martin, Stephen R -- Liu, Junfeng -- Xiao, Haixia -- McCauley, John W -- Locher, Kathrin -- Walker, Philip A -- Collins, Patrick J -- Kawaoka, Yoshihiro -- Skehel, John J -- Gamblin, Steven J -- BB/E010806/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U117512723/Medical Research Council/United Kingdom -- MC_U117584222/Medical Research Council/United Kingdom -- U117512723/Medical Research Council/United Kingdom -- U117570592/Medical Research Council/United Kingdom -- U117584222/Medical Research Council/United Kingdom -- England -- Nature. 2013 May 16;497(7449):392-6. doi: 10.1038/nature12144. Epub 2013 Apr 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23615615" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Birds/metabolism/virology ; Chick Embryo ; Crystallography, X-Ray ; Ferrets/*virology ; Hemagglutinin Glycoproteins, Influenza Virus/*chemistry/genetics/*metabolism ; *Host Specificity ; Humans ; Influenza A Virus, H5N1 Subtype/chemistry/*genetics/*metabolism/pathogenicity ; Models, Biological ; Models, Molecular ; Mutation ; Orthomyxoviridae Infections/*transmission/*virology ; Protein Conformation ; Receptors, Virus/*metabolism ; Species Specificity
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    53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark (2013)
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    Publication Date: 2013-06-14
    Description: 53BP1 (also called TP53BP1) is a chromatin-associated factor that promotes immunoglobulin class switching and DNA double-strand-break (DSB) repair by non-homologous end joining. To accomplish its function in DNA repair, 53BP1 accumulates at DSB sites downstream of the RNF168 ubiquitin ligase. How ubiquitin recruits 53BP1 to break sites remains unknown as its relocalization involves recognition of histone H4 Lys 20 (H4K20) methylation by its Tudor domain. Here we elucidate how vertebrate 53BP1 is recruited to the chromatin that flanks DSB sites. We show that 53BP1 recognizes mononucleosomes containing dimethylated H4K20 (H4K20me2) and H2A ubiquitinated on Lys 15 (H2AK15ub), the latter being a product of RNF168 action on chromatin. 53BP1 binds to nucleosomes minimally as a dimer using its previously characterized methyl-lysine-binding Tudor domain and a carboxy-terminal extension, termed the ubiquitination-dependent recruitment (UDR) motif, which interacts with the epitope formed by H2AK15ub and its surrounding residues on the H2A tail. 53BP1 is therefore a bivalent histone modification reader that recognizes a histone 'code' produced by DSB signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955401/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955401/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fradet-Turcotte, Amelie -- Canny, Marella D -- Escribano-Diaz, Cristina -- Orthwein, Alexandre -- Leung, Charles C Y -- Huang, Hao -- Landry, Marie-Claude -- Kitevski-LeBlanc, Julianne -- Noordermeer, Sylvie M -- Sicheri, Frank -- Durocher, Daniel -- 84297-1/Canadian Institutes of Health Research/Canada -- 84297-2/Canadian Institutes of Health Research/Canada -- MOP84297/Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Jul 4;499(7456):50-4. doi: 10.1038/nature12318. Epub 2013 Jun 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23760478" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Cell Cycle Proteins/chemistry/metabolism ; Cell Line ; Chromosomal Proteins, Non-Histone/chemistry/deficiency/genetics ; DNA Breaks, Double-Stranded ; *DNA Damage ; DNA-Binding Proteins/chemistry/deficiency/genetics ; Female ; Histones/*chemistry/*metabolism ; Humans ; Intracellular Signaling Peptides and ; Proteins/chemistry/deficiency/genetics/*metabolism ; Lysine/*metabolism ; Male ; Mice ; Molecular Sequence Data ; Mutant Proteins/chemistry/metabolism ; Nuclear Proteins/chemistry/metabolism ; Nucleosomes/chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Schizosaccharomyces ; Schizosaccharomyces pombe Proteins/chemistry/metabolism ; Signal Transduction ; Ubiquitin/*metabolism ; *Ubiquitination
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    Structural mechanism of cytosolic DNA sensing by cGAS (2013)
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    Publication Date: 2013-06-01
    Description: Cytosolic DNA arising from intracellular bacterial or viral infections is a powerful pathogen-associated molecular pattern (PAMP) that leads to innate immune host defence by the production of type I interferon and inflammatory cytokines. Recognition of cytosolic DNA by the recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of cGAMP to activate the stimulator of interferon genes (STING). Here we report the crystal structure of cGAS alone and in complex with DNA, ATP and GTP along with functional studies. Our results explain the broad DNA sensing specificity of cGAS, show how cGAS catalyses dinucleotide formation and indicate activation by a DNA-induced structural switch. cGAS possesses a remarkable structural similarity to the antiviral cytosolic double-stranded RNA sensor 2'-5'oligoadenylate synthase (OAS1), but contains a unique zinc thumb that recognizes B-form double-stranded DNA. Our results mechanistically unify dsRNA and dsDNA innate immune sensing by OAS1 and cGAS nucleotidyl transferases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3768140/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3768140/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Civril, Filiz -- Deimling, Tobias -- de Oliveira Mann, Carina C -- Ablasser, Andrea -- Moldt, Manuela -- Witte, Gregor -- Hornung, Veit -- Hopfner, Karl-Peter -- 243046/European Research Council/International -- U19 AI083025/AI/NIAID NIH HHS/ -- U19AI083025/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jun 20;498(7454):332-7. doi: 10.1038/nature12305. Epub 2013 May 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Gene Center, Ludwig-Maximilians-University, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23722159" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/chemistry/metabolism ; Animals ; Base Sequence ; Catalytic Domain ; Crystallography, X-Ray ; *Cytosol ; DNA/chemistry/*metabolism/pharmacology ; Guanosine Triphosphate/chemistry/metabolism ; HEK293 Cells ; Humans ; Membrane Proteins/genetics/metabolism ; Mice ; Models, Biological ; Models, Molecular ; Mutation ; Nucleotidyltransferases/*chemistry/genetics/metabolism ; Protein Conformation/drug effects ; Structure-Activity Relationship ; Substrate Specificity ; Swine ; Uridine Triphosphate/chemistry/metabolism ; Zinc/chemistry/metabolism
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    The initiation of mammalian protein synthesis and mRNA scanning mechanism (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-07-23
    Description: During translation initiation in eukaryotes, the small ribosomal subunit binds messenger RNA at the 5' end and scans in the 5' to 3' direction to locate the initiation codon, form the 80S initiation complex and start protein synthesis. This simple, yet intricate, process is guided by multiple initiation factors. Here we determine the structures of three complexes of the small ribosomal subunit that represent distinct steps in mammalian translation initiation. These structures reveal the locations of eIF1, eIF1A, mRNA and initiator transfer RNA bound to the small ribosomal subunit and provide insights into the details of translation initiation specific to eukaryotes. Conformational changes associated with the captured functional states reveal the dynamics of the interactions in the P site of the ribosome. These results have functional implications for the mechanism of mRNA scanning.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748252/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748252/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lomakin, Ivan B -- Steitz, Thomas A -- GM022778/GM/NIGMS NIH HHS/ -- P01 GM022778/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Aug 15;500(7462):307-11. doi: 10.1038/nature12355. Epub 2013 Jul 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520-8114, USA. ivan.lomakin@yale.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23873042" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Crystallography, X-Ray ; Eukaryotic Initiation Factor-1/chemistry/metabolism ; Humans ; *Models, Molecular ; Protein Binding ; *Protein Biosynthesis ; Protein Structure, Quaternary ; RNA, Messenger/*chemistry/*metabolism ; RNA, Transfer, Met/chemistry/metabolism ; Rabbits ; Ribosome Subunits, Small, Eukaryotic/chemistry/metabolism ; Ribosomes/metabolism
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    Structural basis for the modular recognition of single-stranded RNA by PPR proteins (2013)
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    Publication Date: 2013-10-29
    Description: Pentatricopeptide repeat (PPR) proteins represent a large family of sequence-specific RNA-binding proteins that are involved in multiple aspects of RNA metabolism. PPR proteins, which are found in exceptionally large numbers in the mitochondria and chloroplasts of terrestrial plants, recognize single-stranded RNA (ssRNA) in a modular fashion. The maize chloroplast protein PPR10 binds to two similar RNA sequences from the ATPI-ATPH and PSAJ-RPL33 intergenic regions, referred to as ATPH and PSAJ, respectively. By protecting the target RNA elements from 5' or 3' exonucleases, PPR10 defines the corresponding 5' and 3' messenger RNA termini. Despite rigorous functional characterizations, the structural basis of sequence-specific ssRNA recognition by PPR proteins remains to be elucidated. Here we report the crystal structures of PPR10 in RNA-free and RNA-bound states at resolutions of 2.85 and 2.45 A, respectively. In the absence of RNA binding, the nineteen repeats of PPR10 are assembled into a right-handed superhelical spiral. PPR10 forms an antiparallel, intertwined homodimer and exhibits considerable conformational changes upon binding to its target ssRNA, an 18-nucleotide PSAJ element. Six nucleotides of PSAJ are specifically recognized by six corresponding PPR10 repeats following the predicted code. The molecular basis for the specific and modular recognition of RNA bases A, G and U is revealed. The structural elucidation of RNA recognition by PPR proteins provides an important framework for potential biotechnological applications of PPR proteins in RNA-related research areas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yin, Ping -- Li, Quanxiu -- Yan, Chuangye -- Liu, Ying -- Liu, Junjie -- Yu, Feng -- Wang, Zheng -- Long, Jiafu -- He, Jianhua -- Wang, Hong-Wei -- Wang, Jiawei -- Zhu, Jian-Kang -- Shi, Yigong -- Yan, Nieng -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 5;504(7478):168-71. doi: 10.1038/nature12651. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162847" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; *Models, Molecular ; Plant Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; RNA/chemistry/*metabolism ; Zea mays/*chemistry/genetics/metabolism
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    ATPase-dependent quality control of DNA replication origin licensing (2013)
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    Publication Date: 2013-03-12
    Description: The regulated loading of the Mcm2-7 DNA helicase (comprising six related subunits, Mcm2 to Mcm7) into pre-replicative complexes at multiple replication origins ensures precise once per cell cycle replication in eukaryotic cells. The origin recognition complex (ORC), Cdc6 and Cdt1 load Mcm2-7 into a double hexamer bound around duplex DNA in an ATP-dependent reaction, but the molecular mechanism of this origin 'licensing' is still poorly understood. Here we show that both Mcm2-7 hexamers in Saccharomyces cerevisiae are recruited to origins by an essential, conserved carboxy-terminal domain of Mcm3 that interacts with and stimulates the ATPase activity of ORC-Cdc6. ATP hydrolysis can promote Mcm2-7 loading, but can also promote Mcm2-7 release if components are missing or if ORC has been inactivated by cyclin-dependent kinase phosphorylation. Our work provides new insights into how origins are licensed and reveals a novel ATPase-dependent mechanism contributing to precise once per cell cycle replication.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Frigola, Jordi -- Remus, Dirk -- Mehanna, Amina -- Diffley, John F X -- Cancer Research UK/United Kingdom -- England -- Nature. 2013 Mar 21;495(7441):339-43. doi: 10.1038/nature11920. Epub 2013 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms EN6 3LD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23474987" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*metabolism ; Adenosine Triphosphate/metabolism ; Amino Acid Sequence ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Replication/*genetics ; DNA-Binding Proteins/metabolism ; Enzyme Activation ; Hydrolysis ; Minichromosome Maintenance Complex Component 3 ; Minichromosome Maintenance Complex Component 7 ; Nuclear Proteins/metabolism ; Protein Binding ; Replication Origin/*genetics ; Saccharomyces cerevisiae/cytology/enzymology/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Sequence Alignment
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    Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26 (2013)
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    Publication Date: 2013-07-09
    Description: The newly emergent Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe pulmonary disease in humans, representing the second example of a highly pathogenic coronavirus, the first being SARS-CoV. CD26 (also known as dipeptidyl peptidase 4, DPP4) was recently identified as the cellular receptor for MERS-CoV. The engagement of the MERS-CoV spike protein with CD26 mediates viral attachment to host cells and virus-cell fusion, thereby initiating infection. Here we delineate the molecular basis of this specific interaction by presenting the first crystal structures of both the free receptor binding domain (RBD) of the MERS-CoV spike protein and its complex with CD26. Furthermore, binding between the RBD and CD26 is measured using real-time surface plasmon resonance with a dissociation constant of 16.7 nM. The viral RBD is composed of a core subdomain homologous to that of the SARS-CoV spike protein, and a unique strand-dominated external receptor binding motif that recognizes blades IV and V of the CD26 beta-propeller. The atomic details at the interface between the two binding entities reveal a surprising protein-protein contact mediated mainly by hydrophilic residues. Sequence alignment indicates, among betacoronaviruses, a possible structural conservation for the region homologous to the MERS-CoV RBD core, but a high variation in the external receptor binding motif region for virus-specific pathogenesis such as receptor recognition.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Guangwen -- Hu, Yawei -- Wang, Qihui -- Qi, Jianxun -- Gao, Feng -- Li, Yan -- Zhang, Yanfang -- Zhang, Wei -- Yuan, Yuan -- Bao, Jinku -- Zhang, Buchang -- Shi, Yi -- Yan, Jinghua -- Gao, George F -- England -- Nature. 2013 Aug 8;500(7461):227-31. doi: 10.1038/nature12328. Epub 2013 Jul 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23831647" target="_blank"〉PubMed〈/a〉
    Keywords: Conserved Sequence/genetics ; Coronavirus/*chemistry/genetics/*metabolism ; Dipeptidyl Peptidase 4/*chemistry/metabolism ; Humans ; Protein Binding ; Protein Interaction Domains and Motifs/genetics ; Protein Structure, Tertiary/genetics ; Receptors, Virus/*chemistry/*metabolism ; *Virus Attachment
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    Rotation mechanism of Enterococcus hirae V1-ATPase based on asymmetric crystal structures (2013)
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    Publication Date: 2013-01-22
    Description: In various cellular membrane systems, vacuolar ATPases (V-ATPases) function as proton pumps, which are involved in many processes such as bone resorption and cancer metastasis, and these membrane proteins represent attractive drug targets for osteoporosis and cancer. The hydrophilic V(1) portion is known as a rotary motor, in which a central axis DF complex rotates inside a hexagonally arranged catalytic A(3)B(3) complex using ATP hydrolysis energy, but the molecular mechanism is not well defined owing to a lack of high-resolution structural information. We previously reported on the in vitro expression, purification and reconstitution of Enterococcus hirae V(1)-ATPase from the A(3)B(3) and DF complexes. Here we report the asymmetric structures of the nucleotide-free (2.8 A) and nucleotide-bound (3.4 A) A(3)B(3) complex that demonstrate conformational changes induced by nucleotide binding, suggesting a binding order in the right-handed rotational orientation in a cooperative manner. The crystal structures of the nucleotide-free (2.2 A) and nucleotide-bound (2.7 A) V(1)-ATPase are also reported. The more tightly packed nucleotide-binding site seems to be induced by DF binding, and ATP hydrolysis seems to be stimulated by the approach of a conserved arginine residue. To our knowledge, these asymmetric structures represent the first high-resolution view of the rotational mechanism of V(1)-ATPase.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arai, Satoshi -- Saijo, Shinya -- Suzuki, Kano -- Mizutani, Kenji -- Kakinuma, Yoshimi -- Ishizuka-Katsura, Yoshiko -- Ohsawa, Noboru -- Terada, Takaho -- Shirouzu, Mikako -- Yokoyama, Shigeyuki -- Iwata, So -- Yamato, Ichiro -- Murata, Takeshi -- England -- Nature. 2013 Jan 31;493(7434):703-7. doi: 10.1038/nature11778. Epub 2013 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage, Chiba 263-8522, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23334411" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallization ; Enterococcus/*enzymology/genetics ; *Models, Molecular ; Mutation ; Nucleotides/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits ; Rotation ; Vacuolar Proton-Translocating ATPases/*chemistry/genetics
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    Stepwise acquisition of vocal combinatorial capacity in songbirds and human infants (2013)
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    Publication Date: 2013-05-31
    Description: Human language, as well as birdsong, relies on the ability to arrange vocal elements in new sequences. However, little is known about the ontogenetic origin of this capacity. Here we track the development of vocal combinatorial capacity in three species of vocal learners, combining an experimental approach in zebra finches (Taeniopygia guttata) with an analysis of natural development of vocal transitions in Bengalese finches (Lonchura striata domestica) and pre-lingual human infants. We find a common, stepwise pattern of acquiring vocal transitions across species. In our first study, juvenile zebra finches were trained to perform one song and then the training target was altered, prompting the birds to swap syllable order, or insert a new syllable into a string. All birds solved these permutation tasks in a series of steps, gradually approximating the target sequence by acquiring new pairwise syllable transitions, sometimes too slowly to accomplish the task fully. Similarly, in the more complex songs of Bengalese finches, branching points and bidirectional transitions in song syntax were acquired in a stepwise fashion, starting from a more restrictive set of vocal transitions. The babbling of pre-lingual human infants showed a similar pattern: instead of a single developmental shift from reduplicated to variegated babbling (that is, from repetitive to diverse sequences), we observed multiple shifts, where each new syllable type slowly acquired a diversity of pairwise transitions, asynchronously over development. Collectively, these results point to a common generative process that is conserved across species, suggesting that the long-noted gap between perceptual versus motor combinatorial capabilities in human infants may arise partly from the challenges in constructing new pairwise vocal transitions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676428/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676428/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lipkind, Dina -- Marcus, Gary F -- Bemis, Douglas K -- Sasahara, Kazutoshi -- Jacoby, Nori -- Takahasi, Miki -- Suzuki, Kenta -- Feher, Olga -- Ravbar, Primoz -- Okanoya, Kazuo -- Tchernichovski, Ofer -- R01 DC004722/DC/NIDCD NIH HHS/ -- England -- Nature. 2013 Jun 6;498(7452):104-8. doi: 10.1038/nature12173. Epub 2013 May 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychology, Hunter College, City University of New York, New York, NY 10065, USA. dina.lipkind@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23719373" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Evolution ; *Child Language ; Finches/*physiology ; Humans ; Infant ; Male ; Models, Biological ; Phonetics ; Speech/physiology ; Time Factors ; Vocalization, Animal/*physiology
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    Temporal regulation of EGF signalling networks by the scaffold protein Shc1 (2013)
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    Publication Date: 2013-07-13
    Description: Cell-surface receptors frequently use scaffold proteins to recruit cytoplasmic targets, but the rationale for this is uncertain. Activated receptor tyrosine kinases, for example, engage scaffolds such as Shc1 that contain phosphotyrosine (pTyr)-binding (PTB) domains. Using quantitative mass spectrometry, here we show that mammalian Shc1 responds to epidermal growth factor (EGF) stimulation through multiple waves of distinct phosphorylation events and protein interactions. After stimulation, Shc1 rapidly binds a group of proteins that activate pro-mitogenic or survival pathways dependent on recruitment of the Grb2 adaptor to Shc1 pTyr sites. Akt-mediated feedback phosphorylation of Shc1 Ser 29 then recruits the Ptpn12 tyrosine phosphatase. This is followed by a sub-network of proteins involved in cytoskeletal reorganization, trafficking and signal termination that binds Shc1 with delayed kinetics, largely through the SgK269 pseudokinase/adaptor protein. Ptpn12 acts as a switch to convert Shc1 from pTyr/Grb2-based signalling to SgK269-mediated pathways that regulate cell invasion and morphogenesis. The Shc1 scaffold therefore directs the temporal flow of signalling information after EGF stimulation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Yong -- Zhang, Cunjie -- Croucher, David R -- Soliman, Mohamed A -- St-Denis, Nicole -- Pasculescu, Adrian -- Taylor, Lorne -- Tate, Stephen A -- Hardy, W Rod -- Colwill, Karen -- Dai, Anna Yue -- Bagshaw, Rick -- Dennis, James W -- Gingras, Anne-Claude -- Daly, Roger J -- Pawson, Tony -- MOP-13466-6849/Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Jul 11;499(7457):166-71. doi: 10.1038/nature12308.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto M5G 1X5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23846654" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast/cytology ; Cell Line ; Epidermal Growth Factor/*metabolism ; Epithelial Cells/cytology ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Feedback, Physiological ; GRB2 Adaptor Protein/deficiency/genetics/metabolism ; Humans ; Mice ; Multiprotein Complexes/chemistry/metabolism ; Phosphorylation ; Protein Binding ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins c-akt/metabolism ; Rats ; Receptor, Epidermal Growth Factor/agonists/metabolism ; Shc Signaling Adaptor Proteins/deficiency/genetics/*metabolism ; *Signal Transduction ; Time Factors
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    Carbon catabolite repression of the maltose transporter revealed by X-ray crystallography (2013)
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    Publication Date: 2013-06-19
    Description: Efficient carbon utilization is critical to the survival of microorganisms in competitive environments. To optimize energy usage, bacteria have developed an integrated control system to preferentially uptake carbohydrates that support rapid growth. The availability of a preferred carbon source, such as glucose, represses the synthesis and activities of proteins necessary for the transport and metabolism of secondary carbon sources. This regulatory phenomenon is defined as carbon catabolite repression. In enteric bacteria, the key player of carbon catabolite repression is a component of the glucose-specific phosphotransferase system, enzyme IIA (EIIA(Glc)). It is known that unphosphorylated EIIA(Glc) binds to and inhibits a variety of transporters when glucose is available. However, understanding the underlying molecular mechanism has been hindered by the complete absence of structures for any EIIA(Glc)-transporter complexes. Here we present the 3.9 A crystal structure of Escherichia coli EIIA(Glc) in complex with the maltose transporter, an ATP-binding cassette (ABC) transporter. The structure shows that two EIIA(Glc) molecules bind to the cytoplasmic ATPase subunits, stabilizing the transporter in an inward-facing conformation and preventing the structural rearrangements necessary for ATP hydrolysis. We also show that the half-maximal inhibitory concentrations of the full-length EIIA(Glc) and an amino-terminal truncation mutant differ by 60-fold, consistent with the hypothesis that the amino-terminal region, disordered in the crystal structure, functions as a membrane anchor to increase the effective EIIA(Glc) concentration at the membrane. Together these data suggest a model of how the central regulatory protein EIIA(Glc) allosterically inhibits maltose uptake in E. coli.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875231/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3875231/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Shanshuang -- Oldham, Michael L -- Davidson, Amy L -- Chen, Jue -- GM070515/GM/NIGMS NIH HHS/ -- R01 GM070515/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jul 18;499(7458):364-8. doi: 10.1038/nature12232. Epub 2013 Jun 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23770568" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/*chemistry/metabolism ; Carbon/metabolism ; Crystallography, X-Ray ; Escherichia coli Proteins/*chemistry/metabolism ; Models, Molecular ; Phosphoenolpyruvate Sugar Phosphotransferase System/*chemistry/metabolism
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    Crystal structure of the entire respiratory complex I (2013)
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    Publication Date: 2013-02-19
    Description: Complex I is the first and largest enzyme of the respiratory chain and has a central role in cellular energy production through the coupling of NADH:ubiquinone electron transfer to proton translocation. It is also implicated in many common human neurodegenerative diseases. Here, we report the first crystal structure of the entire, intact complex I (from Thermus thermophilus) at 3.3 A resolution. The structure of the 536-kDa complex comprises 16 different subunits, with a total of 64 transmembrane helices and 9 iron-sulphur clusters. The core fold of subunit Nqo8 (ND1 in humans) is, unexpectedly, similar to a half-channel of the antiporter-like subunits. Small subunits nearby form a linked second half-channel, which completes the fourth proton-translocation pathway (present in addition to the channels in three antiporter-like subunits). The quinone-binding site is unusually long, narrow and enclosed. The quinone headgroup binds at the deep end of this chamber, near iron-sulphur cluster N2. Notably, the chamber is linked to the fourth channel by a 'funnel' of charged residues. The link continues over the entire membrane domain as a flexible central axis of charged and polar residues, and probably has a leading role in the propagation of conformational changes, aided by coupling elements. The structure suggests that a unique, out-of-the-membrane quinone-reaction chamber enables the redox energy to drive concerted long-range conformational changes in the four antiporter-like domains, resulting in translocation of four protons per cycle.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672946/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672946/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baradaran, Rozbeh -- Berrisford, John M -- Minhas, Gurdeep S -- Sazanov, Leonid A -- MC_U105674180/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2013 Feb 28;494(7438):443-8. doi: 10.1038/nature11871. Epub 2013 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23417064" target="_blank"〉PubMed〈/a〉
    Keywords: Benzoquinones/chemistry/metabolism ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Electron Transport Complex I/*chemistry/*metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; NAD/metabolism ; Oxidation-Reduction ; Protein Folding ; Protein Subunits/chemistry/metabolism ; Proton-Motive Force ; Protons ; Thermus thermophilus/*chemistry/cytology ; Ubiquinone/metabolism
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    D14-SCF(D3)-dependent degradation of D53 regulates strigolactone signalling (2013)
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    Publication Date: 2013-12-18
    Description: Strigolactones (SLs), a newly discovered class of carotenoid-derived phytohormones, are essential for developmental processes that shape plant architecture and interactions with parasitic weeds and symbiotic arbuscular mycorrhizal fungi. Despite the rapid progress in elucidating the SL biosynthetic pathway, the perception and signalling mechanisms of SL remain poorly understood. Here we show that DWARF 53 (D53) acts as a repressor of SL signalling and that SLs induce its degradation. We find that the rice (Oryza sativa) d53 mutant, which produces an exaggerated number of tillers compared to wild-type plants, is caused by a gain-of-function mutation and is insensitive to exogenous SL treatment. The D53 gene product shares predicted features with the class I Clp ATPase proteins and can form a complex with the alpha/beta hydrolase protein DWARF 14 (D14) and the F-box protein DWARF 3 (D3), two previously identified signalling components potentially responsible for SL perception. We demonstrate that, in a D14- and D3-dependent manner, SLs induce D53 degradation by the proteasome and abrogate its activity in promoting axillary bud outgrowth. Our combined genetic and biochemical data reveal that D53 acts as a repressor of the SL signalling pathway, whose hormone-induced degradation represents a key molecular link between SL perception and responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096652/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096652/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Feng -- Lin, Qibing -- Zhu, Lihong -- Ren, Yulong -- Zhou, Kunneng -- Shabek, Nitzan -- Wu, Fuqing -- Mao, Haibin -- Dong, Wei -- Gan, Lu -- Ma, Weiwei -- Gao, He -- Chen, Jun -- Yang, Chao -- Wang, Dan -- Tan, Junjie -- Zhang, Xin -- Guo, Xiuping -- Wang, Jiulin -- Jiang, Ling -- Liu, Xi -- Chen, Weiqi -- Chu, Jinfang -- Yan, Cunyu -- Ueno, Kotomi -- Ito, Shinsaku -- Asami, Tadao -- Cheng, Zhijun -- Wang, Jie -- Lei, Cailin -- Zhai, Huqu -- Wu, Chuanyin -- Wang, Haiyang -- Zheng, Ning -- Wan, Jianmin -- R01 CA107134/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 19;504(7480):406-10. doi: 10.1038/nature12878. Epub 2013 Dec 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] National Key Laboratory for Crop Genetics and Germplasm Enhancement, Jiangsu Plant Gene Engineering Research Center, Nanjing Agricultural University, Nanjing 210095, China [2] National Key Facility for Crop Gene Resources and Genetic Improvement, Institute of Crop Science, Chinese Academy of Agricultural Sciences, Beijing 100081, China. ; National Key Facility for Crop Gene Resources and Genetic Improvement, Institute of Crop Science, Chinese Academy of Agricultural Sciences, Beijing 100081, China. ; National Key Laboratory for Crop Genetics and Germplasm Enhancement, Jiangsu Plant Gene Engineering Research Center, Nanjing Agricultural University, Nanjing 210095, China. ; 1] Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA [2] Howard Hughes Medical Institute, Box 357280, University of Washington, Seattle, Washington 98195, USA. ; National Centre for Plant Gene Research (Beijing), Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, 1-2 Beichen West Road, Beijing 100101, China. ; Department of Applied Biological Chemistry, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336215" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cloning, Molecular ; Gene Expression Regulation, Plant ; Lactones/*metabolism ; Molecular Sequence Data ; Mutation/genetics ; Oryza/genetics/*metabolism ; Phenotype ; Plant Growth Regulators/*metabolism ; Plant Proteins/genetics/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; *Proteolysis ; SKP Cullin F-Box Protein Ligases/*metabolism ; *Signal Transduction
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    Follow the crowd (2013)
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    Publication Date: 2013-11-13
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2013 Nov 7;503(7474):6.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24218658" target="_blank"〉PubMed〈/a〉
    Keywords: Electric Stimulation ; Humans ; Hydrodynamics ; *Mass Behavior ; *Microspheres ; Models, Biological ; Plastics ; Static Electricity
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    Reconfiguration of the proteasome during chaperone-mediated assembly (2013)
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    Publication Date: 2013-05-07
    Description: The proteasomal ATPase ring, comprising Rpt1-Rpt6, associates with the heptameric alpha-ring of the proteasome core particle (CP) in the mature proteasome, with the Rpt carboxy-terminal tails inserting into pockets of the alpha-ring. Rpt ring assembly is mediated by four chaperones, each binding a distinct Rpt subunit. Here we report that the base subassembly of the Saccharomyces cerevisiae proteasome, which includes the Rpt ring, forms a high-affinity complex with the CP. This complex is subject to active dissociation by the chaperones Hsm3, Nas6 and Rpn14. Chaperone-mediated dissociation was abrogated by a non-hydrolysable ATP analogue, indicating that chaperone action is coupled to nucleotide hydrolysis by the Rpt ring. Unexpectedly, synthetic Rpt tail peptides bound alpha-pockets with poor specificity, except for Rpt6, which uniquely bound the alpha2/alpha3-pocket. Although the Rpt6 tail is not visualized within an alpha-pocket in mature proteasomes, it inserts into the alpha2/alpha3-pocket in the base-CP complex and is important for complex formation. Thus, the Rpt-CP interface is reconfigured when the lid complex joins the nascent proteasome to form the mature holoenzyme.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3687086/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3687086/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Soyeon -- Li, Xueming -- Kim, Ho Min -- Singh, Chingakham Ranjit -- Tian, Geng -- Hoyt, Martin A -- Lovell, Scott -- Battaile, Kevin P -- Zolkiewski, Michal -- Coffino, Philip -- Roelofs, Jeroen -- Cheng, Yifan -- Finley, Daniel -- 1S10RR026814-01/RR/NCRR NIH HHS/ -- 5P20RR017708/RR/NCRR NIH HHS/ -- 8 P20 GM103420/GM/NIGMS NIH HHS/ -- P20 GM103418/GM/NIGMS NIH HHS/ -- P20 RR016475/RR/NCRR NIH HHS/ -- P20 RR017708/RR/NCRR NIH HHS/ -- R01 GM082893/GM/NIGMS NIH HHS/ -- R01GM045335/GM/NIGMS NIH HHS/ -- R01GM082893/GM/NIGMS NIH HHS/ -- R37GM043601/GM/NIGMS NIH HHS/ -- S10 RR026814/RR/NCRR NIH HHS/ -- England -- Nature. 2013 May 23;497(7450):512-6. doi: 10.1038/nature12123. Epub 2013 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23644457" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/genetics/metabolism ; Adenosine Triphosphate/metabolism ; Binding Sites ; Carrier Proteins/metabolism ; Cryoelectron Microscopy ; Holoenzymes/chemistry/metabolism ; Models, Molecular ; Molecular Chaperones/*metabolism ; Proteasome Endopeptidase Complex/*chemistry/genetics/*metabolism ; Protein Conformation ; Recombinant Fusion Proteins/chemistry/genetics/metabolism ; Saccharomyces cerevisiae/enzymology/genetics/growth & development/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism
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    The Mycobacterium tuberculosis regulatory network and hypoxia (2013)
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    Publication Date: 2013-07-05
    Description: We have taken the first steps towards a complete reconstruction of the Mycobacterium tuberculosis regulatory network based on ChIP-Seq and combined this reconstruction with system-wide profiling of messenger RNAs, proteins, metabolites and lipids during hypoxia and re-aeration. Adaptations to hypoxia are thought to have a prominent role in M. tuberculosis pathogenesis. Using ChIP-Seq combined with expression data from the induction of the same factors, we have reconstructed a draft regulatory network based on 50 transcription factors. This network model revealed a direct interconnection between the hypoxic response, lipid catabolism, lipid anabolism and the production of cell wall lipids. As a validation of this model, in response to oxygen availability we observe substantial alterations in lipid content and changes in gene expression and metabolites in corresponding metabolic pathways. The regulatory network reveals transcription factors underlying these changes, allows us to computationally predict expression changes, and indicates that Rv0081 is a regulatory hub.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087036/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087036/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Galagan, James E -- Minch, Kyle -- Peterson, Matthew -- Lyubetskaya, Anna -- Azizi, Elham -- Sweet, Linsday -- Gomes, Antonio -- Rustad, Tige -- Dolganov, Gregory -- Glotova, Irina -- Abeel, Thomas -- Mahwinney, Chris -- Kennedy, Adam D -- Allard, Rene -- Brabant, William -- Krueger, Andrew -- Jaini, Suma -- Honda, Brent -- Yu, Wen-Han -- Hickey, Mark J -- Zucker, Jeremy -- Garay, Christopher -- Weiner, Brian -- Sisk, Peter -- Stolte, Christian -- Winkler, Jessica K -- Van de Peer, Yves -- Iazzetti, Paul -- Camacho, Diogo -- Dreyfuss, Jonathan -- Liu, Yang -- Dorhoi, Anca -- Mollenkopf, Hans-Joachim -- Drogaris, Paul -- Lamontagne, Julie -- Zhou, Yiyong -- Piquenot, Julie -- Park, Sang Tae -- Raman, Sahadevan -- Kaufmann, Stefan H E -- Mohney, Robert P -- Chelsky, Daniel -- Moody, D Branch -- Sherman, David R -- Schoolnik, Gary K -- HHSN272200800059C/AI/NIAID NIH HHS/ -- HHSN272200800059C/PHS HHS/ -- R01 AI 071155/AI/NIAID NIH HHS/ -- R01 AI071155/AI/NIAID NIH HHS/ -- U19 AI 076217/AI/NIAID NIH HHS/ -- U19 AI076217/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jul 11;499(7457):178-83. doi: 10.1038/nature12337. Epub 2013 Jul 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA. jgalag@bu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23823726" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological ; Anoxia/*genetics/metabolism ; Bacterial Proteins/genetics/metabolism ; Binding Sites ; Chromatin Immunoprecipitation ; Gene Expression Profiling ; *Gene Regulatory Networks/genetics ; Genomics ; Lipid Metabolism/genetics ; Metabolic Networks and Pathways/*genetics ; Models, Biological ; Mycobacterium tuberculosis/drug effects/*genetics/*metabolism/physiology ; Oxygen/pharmacology ; Proteolysis ; RNA, Messenger/genetics/metabolism ; Reproducibility of Results ; Sequence Analysis, DNA ; Transcription Factors/genetics/metabolism ; Tuberculosis/metabolism/microbiology
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    DWARF 53 acts as a repressor of strigolactone signalling in rice (2013)
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    Publication Date: 2013-12-18
    Description: Strigolactones (SLs) are a group of newly identified plant hormones that control plant shoot branching. SL signalling requires the hormone-dependent interaction of DWARF 14 (D14), a probable candidate SL receptor, with DWARF 3 (D3), an F-box component of the Skp-Cullin-F-box (SCF) E3 ubiquitin ligase complex. Here we report the characterization of a dominant SL-insensitive rice (Oryza sativa) mutant dwarf 53 (d53) and the cloning of D53, which encodes a substrate of the SCF(D3) ubiquitination complex and functions as a repressor of SL signalling. Treatments with GR24, a synthetic SL analogue, cause D53 degradation via the proteasome in a manner that requires D14 and the SCF(D3) ubiquitin ligase, whereas the dominant form of D53 is resistant to SL-mediated degradation. Moreover, D53 can interact with transcriptional co-repressors known as TOPLESS-RELATED PROTEINS. Our results suggest a model of SL signalling that involves SL-dependent degradation of the D53 repressor mediated by the D14-D3 complex.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Liang -- Liu, Xue -- Xiong, Guosheng -- Liu, Huihui -- Chen, Fulu -- Wang, Lei -- Meng, Xiangbing -- Liu, Guifu -- Yu, Hong -- Yuan, Yundong -- Yi, Wei -- Zhao, Lihua -- Ma, Honglei -- He, Yuanzheng -- Wu, Zhongshan -- Melcher, Karsten -- Qian, Qian -- Xu, H Eric -- Wang, Yonghong -- Li, Jiayang -- England -- Nature. 2013 Dec 19;504(7480):401-5. doi: 10.1038/nature12870. Epub 2013 Dec 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory of Plant Genomics and National Center for Plant Gene Research (Beijing), Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China [2]. ; State Key Laboratory of Plant Genomics and National Center for Plant Gene Research (Beijing), Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China. ; VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. ; Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, Michigan 49503, USA. ; State Key Laboratory of Rice Biology, China National Rice Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou 310006, China. ; 1] VARI-SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [2] Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, Michigan 49503, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336200" target="_blank"〉PubMed〈/a〉
    Keywords: Cloning, Molecular ; Gene Expression Regulation, Plant ; Lactones/*antagonists & inhibitors/*metabolism ; Models, Biological ; Multiprotein Complexes/chemistry/metabolism ; Mutation/genetics ; Oryza/genetics/*metabolism ; Plant Growth Regulators/antagonists & inhibitors/*metabolism ; Plant Proteins/chemistry/genetics/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; Proteolysis ; *Signal Transduction ; Ubiquitin/metabolism
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    Visualization of an endogenous retinoic acid gradient across embryonic development (2013)
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    Publication Date: 2013-04-09
    Description: In vertebrate development, the body plan is determined by primordial morphogen gradients that suffuse the embryo. Retinoic acid (RA) is an important morphogen involved in patterning the anterior-posterior axis of structures, including the hindbrain and paraxial mesoderm. RA diffuses over long distances, and its activity is spatially restricted by synthesizing and degrading enzymes. However, gradients of endogenous morphogens in live embryos have not been directly observed; indeed, their existence, distribution and requirement for correct patterning remain controversial. Here we report a family of genetically encoded indicators for RA that we have termed GEPRAs (genetically encoded probes for RA). Using the principle of fluorescence resonance energy transfer we engineered the ligand-binding domains of RA receptors to incorporate cyan-emitting and yellow-emitting fluorescent proteins as fluorescence resonance energy transfer donor and acceptor, respectively, for the reliable detection of ambient free RA. We created three GEPRAs with different affinities for RA, enabling the quantitative measurement of physiological RA concentrations. Live imaging of zebrafish embryos at the gastrula and somitogenesis stages revealed a linear concentration gradient of endogenous RA in a two-tailed source-sink arrangement across the embryo. Modelling of the observed linear RA gradient suggests that the rate of RA diffusion exceeds the spatiotemporal dynamics of embryogenesis, resulting in stability to perturbation. Furthermore, we used GEPRAs in combination with genetic and pharmacological perturbations to resolve competing hypotheses on the structure of the RA gradient during hindbrain formation and somitogenesis. Live imaging of endogenous concentration gradients across embryonic development will allow the precise assignment of molecular mechanisms to developmental dynamics and will accelerate the application of approaches based on morphogen gradients to tissue engineering and regenerative medicine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shimozono, Satoshi -- Iimura, Tadahiro -- Kitaguchi, Tetsuya -- Higashijima, Shin-Ichi -- Miyawaki, Atsushi -- England -- Nature. 2013 Apr 18;496(7445):363-6. doi: 10.1038/nature12037. Epub 2013 Apr 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Cell Function Dynamics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-city, Saitama 351-0198, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23563268" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Genetically Modified ; Body Patterning/physiology ; Embryo, Nonmammalian/embryology/metabolism ; Embryonic Development/*physiology ; Fibroblast Growth Factors/genetics/metabolism ; Fluorescence Resonance Energy Transfer ; Gastrula/embryology/metabolism ; HeLa Cells ; Humans ; Models, Biological ; Molecular Probes/analysis/genetics/metabolism ; Molecular Sequence Data ; Rhombencephalon/embryology/metabolism ; Somites/embryology/metabolism ; Substrate Specificity ; Tretinoin/analysis/*metabolism ; Zebrafish/*embryology/*metabolism ; Zebrafish Proteins/genetics/metabolism
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    Structure of the human smoothened receptor bound to an antitumour agent (2013)
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    Publication Date: 2013-05-03
    Description: The smoothened (SMO) receptor, a key signal transducer in the hedgehog signalling pathway, is responsible for the maintenance of normal embryonic development and is implicated in carcinogenesis. It is classified as a class frizzled (class F) G-protein-coupled receptor (GPCR), although the canonical hedgehog signalling pathway involves the GLI transcription factors and the sequence similarity with class A GPCRs is less than 10%. Here we report the crystal structure of the transmembrane domain of the human SMO receptor bound to the small-molecule antagonist LY2940680 at 2.5 A resolution. Although the SMO receptor shares the seven-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure reveals an unusually complex arrangement of long extracellular loops stabilized by four disulphide bonds. The ligand binds at the extracellular end of the seven-transmembrane-helix bundle and forms extensive contacts with the loops.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657389/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657389/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Chong -- Wu, Huixian -- Katritch, Vsevolod -- Han, Gye Won -- Huang, Xi-Ping -- Liu, Wei -- Siu, Fai Yiu -- Roth, Bryan L -- Cherezov, Vadim -- Stevens, Raymond C -- F32 DK088392/DK/NIDDK NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- R01 DA27170/DA/NIDA NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- R01MH61887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- U19 MH82441/MH/NIMH NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 May 16;497(7449):338-43. doi: 10.1038/nature12167. Epub 2013 May 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23636324" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Antineoplastic Agents/*chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Disulfides/chemistry ; Frizzled Receptors/chemistry/classification ; Humans ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Phthalazines/*chemistry/metabolism ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/*chemistry/classification/metabolism ; Structural Homology, Protein
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    Structural basis for action by diverse antidepressants on biogenic amine transporters (2013)
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    Publication Date: 2013-10-15
    Description: The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium- and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904662/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904662/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Hui -- Goehring, April -- Wang, Kevin H -- Penmatsa, Aravind -- Ressler, Ryan -- Gouaux, Eric -- R37 MH070039/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 7;503(7474):141-5. doi: 10.1038/nature12648. Epub 2013 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24121440" target="_blank"〉PubMed〈/a〉
    Keywords: Antidepressive Agents, Second-Generation/metabolism/*pharmacology ; Antidepressive Agents, Tricyclic/metabolism/*pharmacology ; Bacterial Proteins/antagonists & inhibitors/chemistry/genetics/metabolism ; Binding, Competitive/drug effects ; Biogenic Amines/*metabolism ; Chlorides/metabolism ; Crystallography, X-Ray ; Humans ; Mazindol/metabolism/pharmacology ; Models, Molecular ; Mutation ; Norepinephrine/metabolism ; *Plasma Membrane Neurotransmitter Transport Proteins/antagonists & ; inhibitors/chemistry/genetics/metabolism ; Protein Conformation/drug effects ; Recombinant Fusion Proteins/*chemistry/genetics/metabolism ; Reproducibility of Results ; Serotonin Plasma Membrane Transport Proteins/*chemistry/genetics/*metabolism ; Serotonin Uptake Inhibitors/metabolism/*pharmacology ; Sertraline/metabolism/pharmacology ; Sodium/metabolism ; Structure-Activity Relationship
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    PAAR-repeat proteins sharpen and diversify the type VI secretion system spike (2013)
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    Publication Date: 2013-08-09
    Description: The bacterial type VI secretion system (T6SS) is a large multicomponent, dynamic macromolecular machine that has an important role in the ecology of many Gram-negative bacteria. T6SS is responsible for translocation of a wide range of toxic effector molecules, allowing predatory cells to kill both prokaryotic as well as eukaryotic prey cells. The T6SS organelle is functionally analogous to contractile tails of bacteriophages and is thought to attack cells by initially penetrating them with a trimeric protein complex called the VgrG spike. Neither the exact protein composition of the T6SS organelle nor the mechanisms of effector selection and delivery are known. Here we report that proteins from the PAAR (proline-alanine-alanine-arginine) repeat superfamily form a sharp conical extension on the VgrG spike, which is further involved in attaching effector domains to the spike. The crystal structures of two PAAR-repeat proteins bound to VgrG-like partners show that these proteins sharpen the tip of the T6SS spike complex. We demonstrate that PAAR proteins are essential for T6SS-mediated secretion and target cell killing by Vibrio cholerae and Acinetobacter baylyi. Our results indicate a new model of the T6SS organelle in which the VgrG-PAAR spike complex is decorated with multiple effectors that are delivered simultaneously into target cells in a single contraction-driven translocation event.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792578/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792578/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shneider, Mikhail M -- Buth, Sergey A -- Ho, Brian T -- Basler, Marek -- Mekalanos, John J -- Leiman, Petr G -- AI-01845/AI/NIAID NIH HHS/ -- AI-026289/AI/NIAID NIH HHS/ -- R01 AI018045/AI/NIAID NIH HHS/ -- R01 AI026289/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Aug 15;500(7462):350-3. doi: 10.1038/nature12453. Epub 2013 Aug 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ecole Polytechnique Federale de Lausanne (EPFL), BSP-415, 1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23925114" target="_blank"〉PubMed〈/a〉
    Keywords: Acinetobacter/genetics/metabolism ; Bacterial Proteins/*chemistry/*secretion ; Bacterial Secretion Systems/*genetics ; Microsatellite Repeats/*physiology ; Protein Binding ; Vibrio cholerae/genetics/metabolism
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    Computational materials science: Soft heaps and clumpy crystals (2013)
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    Publication Date: 2013-01-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sciortino, Francesco -- Zaccarelli, Emanuela -- England -- Nature. 2013 Jan 3;493(7430):30-1. doi: 10.1038/493030a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23282357" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallization ; DNA/*chemistry ; Dendrimers/*chemistry ; *Models, Chemical ; Models, Molecular ; Quantum Theory
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    The architecture of human general transcription factor TFIID core complex (2013)
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    Publication Date: 2013-01-08
    Description: The initiation of gene transcription by RNA polymerase II is regulated by a plethora of proteins in human cells. The first general transcription factor to bind gene promoters is transcription factor IID (TFIID). TFIID triggers pre-initiation complex formation, functions as a coactivator by interacting with transcriptional activators and reads epigenetic marks. TFIID is a megadalton-sized multiprotein complex composed of TATA-box-binding protein (TBP) and 13 TBP-associated factors (TAFs). Despite its crucial role, the detailed architecture and assembly mechanism of TFIID remain elusive. Histone fold domains are prevalent in TAFs, and histone-like tetramer and octamer structures have been proposed in TFIID. A functional core-TFIID subcomplex was revealed in Drosophila nuclei, consisting of a subset of TAFs (TAF4, TAF5, TAF6, TAF9 and TAF12). These core subunits are thought to be present in two copies in holo-TFIID, in contrast to TBP and other TAFs that are present in a single copy, conveying a transition from symmetry to asymmetry in the TFIID assembly pathway. Here we present the structure of human core-TFIID determined by cryo-electron microscopy at 11.6 A resolution. Our structure reveals a two-fold symmetric, interlaced architecture, with pronounced protrusions, that accommodates all conserved structural features of the TAFs including the histone folds. We further demonstrate that binding of one TAF8-TAF10 complex breaks the original symmetry of core-TFIID. We propose that the resulting asymmetric structure serves as a functional scaffold to nucleate holo-TFIID assembly, by accreting one copy each of the remaining TAFs and TBP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bieniossek, Christoph -- Papai, Gabor -- Schaffitzel, Christiane -- Garzoni, Frederic -- Chaillet, Maxime -- Scheer, Elisabeth -- Papadopoulos, Petros -- Tora, Laszlo -- Schultz, Patrick -- Berger, Imre -- England -- Nature. 2013 Jan 31;493(7434):699-702. doi: 10.1038/nature11791. Epub 2013 Jan 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory Grenoble Outstation, Unit of Virus Host Cell Interactions UVHCI, UJF-CNRS-EMBL Unite Mixte International UMI 3265, 6 rue Jules Horowitz, 38042 Grenoble Cedex 9, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23292512" target="_blank"〉PubMed〈/a〉
    Keywords: Cells, Cultured ; Cryoelectron Microscopy ; HeLa Cells ; Humans ; *Models, Molecular ; Protein Binding ; Protein Structure, Tertiary ; Transcription Factor TFIID/*chemistry/genetics/metabolism
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    Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids (2013)
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    Publication Date: 2013-07-19
    Description: Phosphorylated sphingolipids ceramide-1-phosphate (C1P) and sphingosine-1-phosphate (S1P) have emerged as key regulators of cell growth, survival, migration and inflammation. C1P produced by ceramide kinase is an activator of group IVA cytosolic phospholipase A2alpha (cPLA2alpha), the rate-limiting releaser of arachidonic acid used for pro-inflammatory eicosanoid production, which contributes to disease pathogenesis in asthma or airway hyper-responsiveness, cancer, atherosclerosis and thrombosis. To modulate eicosanoid action and avoid the damaging effects of chronic inflammation, cells require efficient targeting, trafficking and presentation of C1P to specific cellular sites. Vesicular trafficking is likely but non-vesicular mechanisms for C1P sensing, transfer and presentation remain unexplored. Moreover, the molecular basis for selective recognition and binding among signalling lipids with phosphate headgroups, namely C1P, phosphatidic acid or their lyso-derivatives, remains unclear. Here, a ubiquitously expressed lipid transfer protein, human GLTPD1, named here CPTP, is shown to specifically transfer C1P between membranes. Crystal structures establish C1P binding through a novel surface-localized, phosphate headgroup recognition centre connected to an interior hydrophobic pocket that adaptively expands to ensheath differing-length lipid chains using a cleft-like gating mechanism. The two-layer, alpha-helically-dominated 'sandwich' topology identifies CPTP as the prototype for a new glycolipid transfer protein fold subfamily. CPTP resides in the cell cytosol but associates with the trans-Golgi network, nucleus and plasma membrane. RNA interference-induced CPTP depletion elevates C1P steady-state levels and alters Golgi cisternae stack morphology. The resulting C1P decrease in plasma membranes and increase in the Golgi complex stimulates cPLA2alpha release of arachidonic acid, triggering pro-inflammatory eicosanoid generation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951269/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951269/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Simanshu, Dhirendra K -- Kamlekar, Ravi Kanth -- Wijesinghe, Dayanjan S -- Zou, Xianqiong -- Zhai, Xiuhong -- Mishra, Shrawan K -- Molotkovsky, Julian G -- Malinina, Lucy -- Hinchcliffe, Edward H -- Chalfant, Charles E -- Brown, Rhoderick E -- Patel, Dinshaw J -- CA121493/CA/NCI NIH HHS/ -- CA154314/CA/NCI NIH HHS/ -- GM072754/GM/NIGMS NIH HHS/ -- GM45928/GM/NIGMS NIH HHS/ -- I01 BX001792/BX/BLRD VA/ -- R01 CA121493/CA/NCI NIH HHS/ -- R01 CA154314/CA/NCI NIH HHS/ -- R01 GM045928/GM/NIGMS NIH HHS/ -- R01 GM072754/GM/NIGMS NIH HHS/ -- R01 HL072925/HL/NHLBI NIH HHS/ -- S10 OD010641/OD/NIH HHS/ -- T32 008695/PHS HHS/ -- England -- Nature. 2013 Aug 22;500(7463):463-7. doi: 10.1038/nature12332. Epub 2013 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23863933" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoproteins/chemistry ; Arachidonic Acid/metabolism ; Biological Transport ; Carrier Proteins/chemistry/genetics/*metabolism ; Cell Membrane/metabolism ; Cell Nucleus/metabolism ; Ceramides/chemistry/*metabolism ; Crystallography, X-Ray ; Cytosol/metabolism ; Eicosanoids/*metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Mice ; Models, Molecular ; Phosphatidic Acids/chemistry/metabolism ; Protein Conformation ; Protein Folding ; Substrate Specificity ; trans-Golgi Network/metabolism
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    Characterization of H7N9 influenza A viruses isolated from humans (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-07-12
    Description: Avian influenza A viruses rarely infect humans; however, when human infection and subsequent human-to-human transmission occurs, worldwide outbreaks (pandemics) can result. The recent sporadic infections of humans in China with a previously unrecognized avian influenza A virus of the H7N9 subtype (A(H7N9)) have caused concern owing to the appreciable case fatality rate associated with these infections (more than 25%), potential instances of human-to-human transmission, and the lack of pre-existing immunity among humans to viruses of this subtype. Here we characterize two early human A(H7N9) isolates, A/Anhui/1/2013 (H7N9) and A/Shanghai/1/2013 (H7N9); hereafter referred to as Anhui/1 and Shanghai/1, respectively. In mice, Anhui/1 and Shanghai/1 were more pathogenic than a control avian H7N9 virus (A/duck/Gunma/466/2011 (H7N9); Dk/GM466) and a representative pandemic 2009 H1N1 virus (A/California/4/2009 (H1N1pdm09); CA04). Anhui/1, Shanghai/1 and Dk/GM466 replicated well in the nasal turbinates of ferrets. In nonhuman primates, Anhui/1 and Dk/GM466 replicated efficiently in the upper and lower respiratory tracts, whereas the replicative ability of conventional human influenza viruses is typically restricted to the upper respiratory tract of infected primates. By contrast, Anhui/1 did not replicate well in miniature pigs after intranasal inoculation. Critically, Anhui/1 transmitted through respiratory droplets in one of three pairs of ferrets. Glycan arrays showed that Anhui/1, Shanghai/1 and A/Hangzhou/1/2013 (H7N9) (a third human A(H7N9) virus tested in this assay) bind to human virus-type receptors, a property that may be critical for virus transmissibility in ferrets. Anhui/1 was found to be less sensitive in mice to neuraminidase inhibitors than a pandemic H1N1 2009 virus, although both viruses were equally susceptible to an experimental antiviral polymerase inhibitor. The robust replicative ability in mice, ferrets and nonhuman primates and the limited transmissibility in ferrets of Anhui/1 suggest that A(H7N9) viruses have pandemic potential.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891892/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891892/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watanabe, Tokiko -- Kiso, Maki -- Fukuyama, Satoshi -- Nakajima, Noriko -- Imai, Masaki -- Yamada, Shinya -- Murakami, Shin -- Yamayoshi, Seiya -- Iwatsuki-Horimoto, Kiyoko -- Sakoda, Yoshihiro -- Takashita, Emi -- McBride, Ryan -- Noda, Takeshi -- Hatta, Masato -- Imai, Hirotaka -- Zhao, Dongming -- Kishida, Noriko -- Shirakura, Masayuki -- de Vries, Robert P -- Shichinohe, Shintaro -- Okamatsu, Masatoshi -- Tamura, Tomokazu -- Tomita, Yuriko -- Fujimoto, Naomi -- Goto, Kazue -- Katsura, Hiroaki -- Kawakami, Eiryo -- Ishikawa, Izumi -- Watanabe, Shinji -- Ito, Mutsumi -- Sakai-Tagawa, Yuko -- Sugita, Yukihiko -- Uraki, Ryuta -- Yamaji, Reina -- Eisfeld, Amie J -- Zhong, Gongxun -- Fan, Shufang -- Ping, Jihui -- Maher, Eileen A -- Hanson, Anthony -- Uchida, Yuko -- Saito, Takehiko -- Ozawa, Makoto -- Neumann, Gabriele -- Kida, Hiroshi -- Odagiri, Takato -- Paulson, James C -- Hasegawa, Hideki -- Tashiro, Masato -- Kawaoka, Yoshihiro -- AI058113/AI/NIAID NIH HHS/ -- AI099274/AI/NIAID NIH HHS/ -- HHSN266200700010C/AI/NIAID NIH HHS/ -- HHSN266200700010C/PHS HHS/ -- T32 AI078985/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Sep 26;501(7468):551-5. doi: 10.1038/nature12392. Epub 2013 Jul 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama 332-0012, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23842494" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antiviral Agents/pharmacology ; Cells, Cultured ; Chickens/virology ; DNA-Directed RNA Polymerases/antagonists & inhibitors ; Dogs ; Enzyme Inhibitors/pharmacology ; Female ; Ferrets/virology ; Humans ; Influenza A Virus, H1N1 Subtype/drug effects/enzymology ; *Influenza A virus/chemistry/drug effects/isolation & purification/pathogenicity ; Influenza, Human/drug therapy/*virology ; Macaca fascicularis/virology ; Madin Darby Canine Kidney Cells ; Male ; Mice ; Mice, Inbred BALB C ; Models, Molecular ; Monkey Diseases/pathology/virology ; Neuraminidase/antagonists & inhibitors ; Orthomyxoviridae Infections/pathology/transmission/*virology ; Quail/virology ; Swine/virology ; Swine, Miniature/virology ; *Virus Replication/drug effects
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    Precision is essential for efficient catalysis in an evolved Kemp eliminase (2013)
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    Publication Date: 2013-10-18
    Description: Linus Pauling established the conceptual framework for understanding and mimicking enzymes more than six decades ago. The notion that enzymes selectively stabilize the rate-limiting transition state of the catalysed reaction relative to the bound ground state reduces the problem of design to one of molecular recognition. Nevertheless, past attempts to capitalize on this idea, for example by using transition state analogues to elicit antibodies with catalytic activities, have generally failed to deliver true enzymatic rates. The advent of computational design approaches, combined with directed evolution, has provided an opportunity to revisit this problem. Starting from a computationally designed catalyst for the Kemp elimination--a well-studied model system for proton transfer from carbon--we show that an artificial enzyme can be evolved that accelerates an elementary chemical reaction 6 x 10(8)-fold, approaching the exceptional efficiency of highly optimized natural enzymes such as triosephosphate isomerase. A 1.09 A resolution crystal structure of the evolved enzyme indicates that familiar catalytic strategies such as shape complementarity and precisely placed catalytic groups can be successfully harnessed to afford such high rate accelerations, making us optimistic about the prospects of designing more sophisticated catalysts.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blomberg, Rebecca -- Kries, Hajo -- Pinkas, Daniel M -- Mittl, Peer R E -- Grutter, Markus G -- Privett, Heidi K -- Mayo, Stephen L -- Hilvert, Donald -- England -- Nature. 2013 Nov 21;503(7476):418-21. doi: 10.1038/nature12623. Epub 2013 Oct 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Organic Chemistry, ETH Zurich, 8093 Zurich, Switzerland [2] Corporate RD Division, Firmenich SA, 1211 Geneva, Switzerland (R.B.); Protabit, Pasadena, California 91101, USA (H.K.P.).〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24132235" target="_blank"〉PubMed〈/a〉
    Keywords: *Biocatalysis ; Carbon/chemistry ; Catalytic Domain ; Crystallography, X-Ray ; *Directed Molecular Evolution ; Enzymes/*chemistry/genetics/*metabolism ; Kinetics ; Models, Molecular ; *Protein Engineering ; Protons ; Triazoles/chemistry/metabolism ; Triose-Phosphate Isomerase/metabolism
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    Sensory biology: A whiff of genome (2013)
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    Publication Date: 2013-04-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boehm, Thomas -- England -- Nature. 2013 Apr 18;496(7445):304-5. doi: 10.1038/496304a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23598335" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Genetic Variation ; Genome/*genetics ; *Heredity ; Ligands ; Major Histocompatibility Complex/genetics/immunology ; Mice ; Models, Biological ; Peptides/chemistry/genetics/urine ; Proteins/analysis/chemistry/genetics ; Proteolysis ; Sensory Receptor Cells/metabolism ; Smell/*physiology
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    Visualizing virus assembly intermediates inside marine cyanobacteria (2013)
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    Publication Date: 2013-10-11
    Description: Cyanobacteria are photosynthetic organisms responsible for approximately 25% of organic carbon fixation on the Earth. These bacteria began to convert solar energy and carbon dioxide into bioenergy and oxygen more than two billion years ago. Cyanophages, which infect these bacteria, have an important role in regulating the marine ecosystem by controlling cyanobacteria community organization and mediating lateral gene transfer. Here we visualize the maturation process of cyanophage Syn5 inside its host cell, Synechococcus, using Zernike phase contrast electron cryo-tomography (cryoET). This imaging modality yields dramatic enhancement of image contrast over conventional cryoET and thus facilitates the direct identification of subcellular components, including thylakoid membranes, carboxysomes and polyribosomes, as well as phages, inside the congested cytosol of the infected cell. By correlating the structural features and relative abundance of viral progeny within cells at different stages of infection, we identify distinct Syn5 assembly intermediates. Our results indicate that the procapsid releases scaffolding proteins and expands its volume at an early stage of genome packaging. Later in the assembly process, we detected full particles with a tail either with or without an additional horn. The morphogenetic pathway we describe here is highly conserved and was probably established long before that of double-stranded DNA viruses infecting more complex organisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984937/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984937/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dai, Wei -- Fu, Caroline -- Raytcheva, Desislava -- Flanagan, John -- Khant, Htet A -- Liu, Xiangan -- Rochat, Ryan H -- Haase-Pettingell, Cameron -- Piret, Jacqueline -- Ludtke, Steve J -- Nagayama, Kuniaki -- Schmid, Michael F -- King, Jonathan A -- Chiu, Wah -- AI0175208/AI/NIAID NIH HHS/ -- GM080139/GM/NIGMS NIH HHS/ -- P41 GM103832/GM/NIGMS NIH HHS/ -- P41GM123832/GM/NIGMS NIH HHS/ -- PN2 EY016525/EY/NEI NIH HHS/ -- PN2EY016525/EY/NEI NIH HHS/ -- R01 GM080139/GM/NIGMS NIH HHS/ -- R56 AI075208/AI/NIAID NIH HHS/ -- T15 LM007093/LM/NLM NIH HHS/ -- T15LM007093/LM/NLM NIH HHS/ -- T32GM007330/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Oct 31;502(7473):707-10. doi: 10.1038/nature12604. Epub 2013 Oct 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Center for Macromolecular Imaging, Verna and Marrs Mclean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24107993" target="_blank"〉PubMed〈/a〉
    Keywords: Aquatic Organisms/cytology/ultrastructure/virology ; Bacteriophages/*growth & development/*ultrastructure ; Cryoelectron Microscopy/*methods ; Electron Microscope Tomography/*methods ; Models, Biological ; Synechococcus/cytology/*ultrastructure/*virology ; *Virus Assembly
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    A directional switch of integrin signalling and a new anti-thrombotic strategy (2013)
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    Publication Date: 2013-10-29
    Description: Integrins have a critical role in thrombosis and haemostasis. Antagonists of the platelet integrin alphaIIbbeta3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding. It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally. Inside-out signalling activates integrins through a talin-dependent mechanism. Integrin ligation mediates thrombus formation and outside-in signalling, which requires Galpha13 and greatly expands thrombi. Here we show that Galpha13 and talin bind to mutually exclusive but distinct sites within the integrin beta3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand-induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and Galpha13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of Galpha13-integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823815/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823815/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shen, Bo -- Zhao, Xiaojuan -- O'Brien, Kelly A -- Stojanovic-Terpo, Aleksandra -- Delaney, M Keegan -- Kim, Kyungho -- Cho, Jaehyung -- Lam, Stephen C-T -- Du, Xiaoping -- HL062350/HL/NHLBI NIH HHS/ -- HL080264/HL/NHLBI NIH HHS/ -- HL109439/HL/NHLBI NIH HHS/ -- R01 HL080264/HL/NHLBI NIH HHS/ -- R01 HL109439/HL/NHLBI NIH HHS/ -- T32 HL007829/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Nov 7;503(7474):131-5. doi: 10.1038/nature12613. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, Illinois 60612, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162846" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Antithrombins/adverse effects/*pharmacology/therapeutic use ; Binding Sites ; Bleeding Time ; *Cell Polarity ; Cytoplasm/metabolism ; GTP-Binding Protein alpha Subunits, G12-G13/metabolism ; Hemorrhage/chemically induced ; Humans ; Integrin beta3/chemistry/genetics/metabolism ; Integrins/chemistry/deficiency/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Platelet Glycoprotein GPIIb-IIIa Complex/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Signal Transduction/*drug effects ; Talin/metabolism ; Thrombosis/*drug therapy/metabolism/pathology
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    Climate science: Plant a tree, but tend it well (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-06-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pongratz, Julia -- England -- Nature. 2013 Jun 6;498(7452):47-8. doi: 10.1038/498047a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23739422" target="_blank"〉PubMed〈/a〉
    Keywords: Atmosphere/chemistry ; Carbon Dioxide/metabolism ; *Carbon Sequestration ; Climate Change/statistics & numerical data ; Ecology/*methods ; *Forestry/methods ; Human Activities ; Models, Biological ; Nitrogen/analysis/*metabolism ; Nitrogen Fixation ; Soil Microbiology ; Trees/growth & development/*metabolism ; Uncertainty
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    Structure-guided discovery of the metabolite carboxy-SAM that modulates tRNA function (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-05-17
    Description: The identification of novel metabolites and the characterization of their biological functions are major challenges in biology. X-ray crystallography can reveal unanticipated ligands that persist through purification and crystallization. These adventitious protein-ligand complexes provide insights into new activities, pathways and regulatory mechanisms. We describe a new metabolite, carboxy-S-adenosyl-l-methionine (Cx-SAM), its biosynthetic pathway and its role in transfer RNA modification. The structure of CmoA, a member of the SAM-dependent methyltransferase superfamily, revealed a ligand consistent with Cx-SAM in the catalytic site. Mechanistic analyses showed an unprecedented role for prephenate as the carboxyl donor and the involvement of a unique ylide intermediate as the carboxyl acceptor in the CmoA-mediated conversion of SAM to Cx-SAM. A second member of the SAM-dependent methyltransferase superfamily, CmoB, recognizes Cx-SAM and acts as a carboxymethyltransferase to convert 5-hydroxyuridine into 5-oxyacetyl uridine at the wobble position of multiple tRNAs in Gram-negative bacteria, resulting in expanded codon-recognition properties. CmoA and CmoB represent the first documented synthase and transferase for Cx-SAM. These findings reveal new functional diversity in the SAM-dependent methyltransferase superfamily and expand the metabolic and biological contributions of SAM-based biochemistry. These discoveries highlight the value of structural genomics approaches in identifying ligands within the context of their physiologically relevant macromolecular binding partners, and in revealing their functions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895326/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895326/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jungwook -- Xiao, Hui -- Bonanno, Jeffrey B -- Kalyanaraman, Chakrapani -- Brown, Shoshana -- Tang, Xiangying -- Al-Obaidi, Nawar F -- Patskovsky, Yury -- Babbitt, Patricia C -- Jacobson, Matthew P -- Lee, Young-Sam -- Almo, Steven C -- GM093342/GM/NIGMS NIH HHS/ -- GM094662/GM/NIGMS NIH HHS/ -- P30-EB-009998/EB/NIBIB NIH HHS/ -- U54 GM093342/GM/NIGMS NIH HHS/ -- U54 GM094662/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jun 6;498(7452):123-6. doi: 10.1038/nature12180. Epub 2013 May 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA. jungwook.kim@einstein.yu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23676670" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Biosynthetic Pathways ; Catalytic Domain ; Crystallography, X-Ray ; Cyclohexanecarboxylic Acids/metabolism ; Cyclohexenes/metabolism ; Escherichia coli/enzymology ; Escherichia coli Proteins/chemistry/genetics/*metabolism ; Ligands ; Methyltransferases/deficiency/genetics/*metabolism ; Models, Molecular ; Molecular Weight ; One-Carbon Group Transferases/chemistry/*metabolism ; Protein Multimerization ; Protein Structure, Secondary ; RNA, Bacterial/chemistry/genetics/metabolism ; RNA, Transfer/chemistry/*genetics/*metabolism ; S-Adenosylmethionine/*analogs & derivatives/biosynthesis/*chemistry/*metabolism ; Uridine/analogs & derivatives/chemistry/metabolism
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    Rats maintain an overhead binocular field at the expense of constant fusion (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-05-28
    Description: Fusing left and right eye images into a single view is dependent on precise ocular alignment, which relies on coordinated eye movements. During movements of the head this alignment is maintained by numerous reflexes. Although rodents share with other mammals the key components of eye movement control, the coordination of eye movements in freely moving rodents is unknown. Here we show that movements of the two eyes in freely moving rats differ fundamentally from the precisely controlled eye movements used by other mammals to maintain continuous binocular fusion. The observed eye movements serve to keep the visual fields of the two eyes continuously overlapping above the animal during free movement, but not continuously aligned. Overhead visual stimuli presented to rats freely exploring an open arena evoke an immediate shelter-seeking behaviour, but are ineffective when presented beside the arena. We suggest that continuously overlapping visual fields overhead would be of evolutionary benefit for predator detection by minimizing blind spots.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wallace, Damian J -- Greenberg, David S -- Sawinski, Juergen -- Rulla, Stefanie -- Notaro, Giuseppe -- Kerr, Jason N D -- England -- Nature. 2013 Jun 6;498(7452):65-9. doi: 10.1038/nature12153. Epub 2013 May 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Network Imaging Group, Max Planck Institute for Biological Cybernetics, Spemannstrasse 41, 72076 Tubingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23708965" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Escape Reaction/physiology ; Exploratory Behavior/physiology ; Eye Movements/physiology ; Head/physiology ; Models, Biological ; Movement/physiology ; Optic Disk/physiology ; Predatory Behavior ; Rats ; Retina/physiology ; Vision, Binocular/*physiology ; Visual Fields/*physiology
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    Targeting Plasmodium PI(4)K to eliminate malaria (2013)
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    Publication Date: 2013-11-29
    Description: Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940870/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3940870/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McNamara, Case W -- Lee, Marcus C S -- Lim, Chek Shik -- Lim, Siau Hoi -- Roland, Jason -- Nagle, Advait -- Simon, Oliver -- Yeung, Bryan K S -- Chatterjee, Arnab K -- McCormack, Susan L -- Manary, Micah J -- Zeeman, Anne-Marie -- Dechering, Koen J -- Kumar, T R Santha -- Henrich, Philipp P -- Gagaring, Kerstin -- Ibanez, Maureen -- Kato, Nobutaka -- Kuhen, Kelli L -- Fischli, Christoph -- Rottmann, Matthias -- Plouffe, David M -- Bursulaya, Badry -- Meister, Stephan -- Rameh, Lucia -- Trappe, Joerg -- Haasen, Dorothea -- Timmerman, Martijn -- Sauerwein, Robert W -- Suwanarusk, Rossarin -- Russell, Bruce -- Renia, Laurent -- Nosten, Francois -- Tully, David C -- Kocken, Clemens H M -- Glynne, Richard J -- Bodenreider, Christophe -- Fidock, David A -- Diagana, Thierry T -- Winzeler, Elizabeth A -- 078285/Wellcome Trust/United Kingdom -- 089275/Wellcome Trust/United Kingdom -- 090534/Wellcome Trust/United Kingdom -- 096157/Wellcome Trust/United Kingdom -- R01 AI079709/AI/NIAID NIH HHS/ -- R01 AI085584/AI/NIAID NIH HHS/ -- R01 AI090141/AI/NIAID NIH HHS/ -- R01 AI103058/AI/NIAID NIH HHS/ -- R01079709/PHS HHS/ -- R01085584/PHS HHS/ -- R01AI090141/AI/NIAID NIH HHS/ -- WT078285/Wellcome Trust/United Kingdom -- WT096157/Wellcome Trust/United Kingdom -- England -- Nature. 2013 Dec 12;504(7479):248-53. doi: 10.1038/nature12782. Epub 2013 Nov 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA [2]. ; 1] Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA [2]. ; Novartis Institutes for Tropical Disease, 138670 Singapore. ; Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA. ; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA. ; Department of Parasitology, Biomedical Primate Research Centre, PO Box 3306, 2280 GH Rijswijk, The Netherlands. ; TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands. ; Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA. ; Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland. ; 1] Swiss Tropical and Public Health Institute, CH-4002 Basel, Switzerland [2] University of Basel, CH-4003 Basel, Switzerland. ; Department of Medicine, School of Medicine, Boston University, Boston, Massachusetts 02118, USA. ; Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland. ; 1] TropIQ Health Sciences, 6525 GA Nijmegen, The Netherlands [2] Department of Medical Microbiology, Radboud University, Nijmegen Medical CentrePO Box 9101, 6500 HB Nijmegen, The Netherlands. ; Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore. ; 1] Laboratory of Malaria Immunobiology, Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Biopolis, 138648 Singapore [2] Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, 117545 Singapore. ; 1] Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK [2] Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot 63110, Thailand. ; 1] Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York 10032, USA [2] Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA. ; 1] Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA [2] Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24284631" target="_blank"〉PubMed〈/a〉
    Keywords: 1-Phosphatidylinositol 4-Kinase/*antagonists & ; inhibitors/chemistry/genetics/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Binding Sites ; Cytokinesis/drug effects ; Drug Resistance/drug effects/genetics ; Fatty Acids/metabolism ; Female ; Hepatocytes/parasitology ; Humans ; Imidazoles/metabolism/pharmacology ; Life Cycle Stages/drug effects ; Macaca mulatta ; Malaria/*drug therapy/*parasitology ; Male ; Models, Biological ; Models, Molecular ; Phosphatidylinositol Phosphates/metabolism ; Plasmodium/classification/*drug effects/*enzymology/growth & development ; Pyrazoles/metabolism/pharmacology ; Quinoxalines/metabolism/pharmacology ; Reproducibility of Results ; Schizonts/cytology/drug effects ; rab GTP-Binding Proteins/genetics/metabolism
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    Coupled GTPase and remodelling ATPase activities form a checkpoint for ribosome export (2013)
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    Publication Date: 2013-11-19
    Description: Eukaryotic ribosomes are assembled by a complex pathway that extends from the nucleolus to the cytoplasm and is powered by many energy-consuming enzymes. Nuclear export is a key, irreversible step in pre-ribosome maturation, but mechanisms underlying the timely acquisition of export competence remain poorly understood. Here we show that a conserved Saccharomyces cerevisiae GTPase Nug2 (also known as Nog2, and as NGP-1, GNL2 or nucleostemin 2 in human) has a key role in the timing of export competence. Nug2 binds the inter-subunit face of maturing, nucleoplasmic pre-60S particles, and the location clashes with the position of Nmd3, a key pre-60S export adaptor. Nug2 and Nmd3 are not present on the same pre-60S particles, with Nug2 binding before Nmd3. Depletion of Nug2 causes premature Nmd3 binding to the pre-60S particles, whereas mutations in the G-domain of Nug2 block Nmd3 recruitment, resulting in severe 60S export defects. Two pre-60S remodelling factors, the Rea1 ATPase and its co-substrate Rsa4, are present on Nug2-associated particles, and both show synthetic lethal interactions with nug2 mutants. Release of Nug2 from pre-60S particles requires both its K(+)-dependent GTPase activity and the remodelling ATPase activity of Rea1. We conclude that Nug2 is a regulatory GTPase that monitors pre-60S maturation, with release from its placeholder site linked to recruitment of the nuclear export machinery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880858/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880858/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Matsuo, Yoshitaka -- Granneman, Sander -- Thoms, Matthias -- Manikas, Rizos-Georgios -- Tollervey, David -- Hurt, Ed -- 077248/Wellcome Trust/United Kingdom -- 092076/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Jan 2;505(7481):112-6. doi: 10.1038/nature12731. Epub 2013 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biochemie-Zentrum der Universitat Heidelberg, Im Neuenheimer Feld 328, Heidelberg D-69120, Germany. ; 1] Wellcome Trust Centre for Cell Biology, The University of Edinburgh, Edinburgh EH9 3JR, UK [2] Centre for Synthetic and Systems Biology, The University of Edinburgh, Edinburgh EH9 3JD, UK [3]. ; 1] Biochemie-Zentrum der Universitat Heidelberg, Im Neuenheimer Feld 328, Heidelberg D-69120, Germany [2]. ; Wellcome Trust Centre for Cell Biology, The University of Edinburgh, Edinburgh EH9 3JR, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24240281" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*metabolism ; Cell Nucleus/*metabolism/secretion ; Cytoplasm/metabolism ; GTP Phosphohydrolases/chemistry/genetics/*metabolism ; Genes, Lethal/genetics ; Models, Molecular ; Mutation/genetics ; Potassium/metabolism ; Protein Binding ; Protein Structure, Tertiary/genetics ; RNA-Binding Proteins/chemistry/metabolism ; Ribosomal Proteins/metabolism ; Ribosome Subunits, Large, Eukaryotic/chemistry/metabolism ; Ribosomes/*chemistry/*metabolism/secretion ; Saccharomyces cerevisiae/cytology/enzymology/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/*metabolism/secretion
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    Icosahedral bacteriophage PhiX174 forms a tail for DNA transport during infection (2013)
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    Publication Date: 2013-12-18
    Description: Prokaryotic viruses have evolved various mechanisms to transport their genomes across bacterial cell walls. Many bacteriophages use a tail to perform this function, whereas tail-less phages rely on host organelles. However, the tail-less, icosahedral, single-stranded DNA PhiX174-like coliphages do not fall into these well-defined infection processes. For these phages, DNA delivery requires a DNA pilot protein. Here we show that the PhiX174 pilot protein H oligomerizes to form a tube whose function is most probably to deliver the DNA genome across the host's periplasmic space to the cytoplasm. The 2.4 A resolution crystal structure of the in vitro assembled H protein's central domain consists of a 170 A-long alpha-helical barrel. The tube is constructed of ten alpha-helices with their amino termini arrayed in a right-handed super-helical coiled-coil and their carboxy termini arrayed in a left-handed super-helical coiled-coil. Genetic and biochemical studies demonstrate that the tube is essential for infectivity but does not affect in vivo virus assembly. Cryo-electron tomograms show that tubes span the periplasmic space and are present while the genome is being delivered into the host cell's cytoplasm. Both ends of the H protein contain transmembrane domains, which anchor the assembled tubes into the inner and outer cell membranes. The central channel of the H-protein tube is lined with amide and guanidinium side chains. This may be a general property of viral DNA conduits and is likely to be critical for efficient genome translocation into the host.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Lei -- Young, Lindsey N -- Zhang, Xinzheng -- Boudko, Sergei P -- Fokine, Andrei -- Zbornik, Erica -- Roznowski, Aaron P -- Molineux, Ian J -- Rossmann, Michael G -- Fane, Bentley A -- England -- Nature. 2014 Jan 16;505(7483):432-5. doi: 10.1038/nature12816. Epub 2013 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA [2]. ; 1] School of Plant Sciences and the BIO5 Institute, University of Arizona, Tucson, Arizona 85721, USA [2]. ; 1] Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA [2] The Research Department, Shriner's Hospital for Children, Portland, Oregon 97239, USA. ; Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA. ; School of Plant Sciences and the BIO5 Institute, University of Arizona, Tucson, Arizona 85721, USA. ; Molecular Genetics and Microbiology, Institute for Cell and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336205" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteriophage phi X 174/*chemistry/*metabolism/ultrastructure ; Biological Transport ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Cytoplasm/metabolism/ultrastructure/virology ; DNA, Viral/*metabolism/ultrastructure ; Escherichia coli/cytology/ultrastructure/*virology ; Genome, Viral ; Models, Molecular ; Periplasm/metabolism/ultrastructure ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Viral Proteins/chemistry/metabolism/ultrastructure ; *Virus Assembly
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    Muc5b is required for airway defence (2013)
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    Publication Date: 2013-12-10
    Description: Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001806/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001806/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roy, Michelle G -- Livraghi-Butrico, Alessandra -- Fletcher, Ashley A -- McElwee, Melissa M -- Evans, Scott E -- Boerner, Ryan M -- Alexander, Samantha N -- Bellinghausen, Lindsey K -- Song, Alfred S -- Petrova, Youlia M -- Tuvim, Michael J -- Adachi, Roberto -- Romo, Irlanda -- Bordt, Andrea S -- Bowden, M Gabriela -- Sisson, Joseph H -- Woodruff, Prescott G -- Thornton, David J -- Rousseau, Karine -- De la Garza, Maria M -- Moghaddam, Seyed J -- Karmouty-Quintana, Harry -- Blackburn, Michael R -- Drouin, Scott M -- Davis, C William -- Terrell, Kristy A -- Grubb, Barbara R -- O'Neal, Wanda K -- Flores, Sonia C -- Cota-Gomez, Adela -- Lozupone, Catherine A -- Donnelly, Jody M -- Watson, Alan M -- Hennessy, Corinne E -- Keith, Rebecca C -- Yang, Ivana V -- Barthel, Lea -- Henson, Peter M -- Janssen, William J -- Schwartz, David A -- Boucher, Richard C -- Dickey, Burton F -- Evans, Christopher M -- CA016086/CA/NCI NIH HHS/ -- CA016672/CA/NCI NIH HHS/ -- CA046934/CA/NCI NIH HHS/ -- G1000450/Medical Research Council/United Kingdom -- K01 DK090285/DK/NIDDK NIH HHS/ -- P01 HL108808/HL/NHLBI NIH HHS/ -- P01 HL110873/HL/NHLBI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P30 CA046934/CA/NCI NIH HHS/ -- P30 DK065988/DK/NIDDK NIH HHS/ -- P30DK065988/DK/NIDDK NIH HHS/ -- P50 HL107168/HL/NHLBI NIH HHS/ -- R01 AA008769/AA/NIAAA NIH HHS/ -- R01 HL080396/HL/NHLBI NIH HHS/ -- R01 HL097000/HL/NHLBI NIH HHS/ -- R01 HL109517/HL/NHLBI NIH HHS/ -- R01 HL114381/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Jan 16;505(7483):412-6. doi: 10.1038/nature12807. Epub 2013 Dec 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2]. ; 1] University of North Carolina-Chapel Hill, 7011 Thurston-Bowles Building, Chapel Hill, North Carolina 27599, USA [2]. ; 1] University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA [2]. ; University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; University of Texas Health Science Center-Houston Medical School, 6431 Fannin Street, Houston, Texas 77030, USA. ; 1] University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Instituto Tecnologico y de Estudios Superiores de Monterrey, Avenida Eugenio Garza Sada 2501 Sur Colonia Tecnologico, Monterrey, Nuevo Leon 64849, Mexico. ; Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, Texas 77030, USA. ; 1] Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, Texas 77030, USA [2] University of Houston-Downtown, 1 Main Street, Houston, Texas 77002, USA. ; University of Nebraska Medical Center, 985910 Nebraska Medical Center, Omaha, Nebraska 68198, USA. ; University of California San Francisco, 505 Parnassus Avenue, San Francisco, California 27599, USA. ; University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK. ; University of North Carolina-Chapel Hill, 7011 Thurston-Bowles Building, Chapel Hill, North Carolina 27599, USA. ; University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA. ; 1] University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA [2] National Jewish Health, Denver, Colorado 80206, USA. ; 1] University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] University of Colorado School of Medicine, 12700 East 19th Avenue, Aurora, Colorado 80045, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24317696" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Asthma/immunology/metabolism ; Bacterial Infections/immunology/microbiology ; Cilia/physiology ; Ear, Middle/immunology/microbiology ; Female ; Inflammation/pathology ; Lung/*immunology/metabolism/microbiology ; Macrophages/immunology/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Models, Biological ; Mucin 5AC/deficiency/metabolism ; Mucin-5B/deficiency/genetics/*metabolism/secretion ; Phagocytosis ; Pulmonary Disease, Chronic Obstructive/immunology/microbiology ; Respiratory Mucosa/*immunology/*metabolism ; Staphylococcus aureus/immunology ; Survival Analysis
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    Structural basis of the alternating-access mechanism in a bile acid transporter (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-12-10
    Description: Bile acids are synthesized from cholesterol in hepatocytes and secreted through the biliary tract into the small intestine, where they aid in absorption of lipids and fat-soluble vitamins. Through a process known as enterohepatic recirculation, more than 90% of secreted bile acids are then retrieved from the intestine and returned to the liver for resecretion. In humans, there are two Na(+)-dependent bile acid transporters involved in enterohepatic recirculation, the Na(+)-taurocholate co-transporting polypeptide (NTCP; also known as SLC10A1) expressed in hepatocytes, and the apical sodium-dependent bile acid transporter (ASBT; also known as SLC10A2) expressed on enterocytes in the terminal ileum. In recent years, ASBT has attracted much interest as a potential drug target for treatment of hypercholesterolaemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing bile acid synthesis and consequently cholesterol consumption. However, a lack of three-dimensional structures of bile acid transporters hampers our ability to understand the molecular mechanisms of substrate selectivity and transport, and to interpret the wealth of existing functional data. The crystal structure of an ASBT homologue from Neisseria meningitidis (ASBT(NM)) in detergent was reported recently, showing the protein in an inward-open conformation bound to two Na(+) and a taurocholic acid. However, the structural changes that bring bile acid and Na(+) across the membrane are difficult to infer from a single structure. To understand the structural changes associated with the coupled transport of Na(+) and bile acids, here we solved two structures of an ASBT homologue from Yersinia frederiksenii (ASBTYf) in a lipid environment, which reveal that a large rigid-body rotation of a substrate-binding domain gives the conserved 'crossover' region, where two discontinuous helices cross each other, alternating accessibility from either side of the cell membrane. This result has implications for the location and orientation of the bile acid during transport, as well as for the translocation pathway for Na(+).〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142352/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142352/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Xiaoming -- Levin, Elena J -- Pan, Yaping -- McCoy, Jason G -- Sharma, Ruchika -- Kloss, Brian -- Bruni, Renato -- Quick, Matthias -- Zhou, Ming -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 GM098878/GM/NIGMS NIH HHS/ -- R01DK088057/DK/NIDDK NIH HHS/ -- R01GM098878/GM/NIGMS NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54 GM087519/GM/NIGMS NIH HHS/ -- U54 GM095315/GM/NIGMS NIH HHS/ -- U54GM087519/GM/NIGMS NIH HHS/ -- U54GM095315/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jan 23;505(7484):569-73. doi: 10.1038/nature12811. Epub 2013 Dec 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [3]. ; 1] Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2]. ; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA. ; New York Consortium on Membrane Protein Structure, New York, New York 10027, USA. ; 1] Department of Psychiatry and Center for Molecular Recognition, Columbia University, New York, New York 10032, USA [2] New York State Psychiatric Institute, Division of Molecular Therapeutics, New York, New York 10032, USA. ; 1] Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA [2] Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA [3] Ion Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24317697" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; Bile Acids and Salts/metabolism ; Biological Transport ; Carrier Proteins/*chemistry/*metabolism ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Membrane Glycoproteins/*chemistry/*metabolism ; Models, Molecular ; Protein Conformation ; Reproducibility of Results ; Rotation ; Sodium/metabolism ; Structure-Activity Relationship ; Yersinia/*chemistry
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    Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-19
    Description: Botulinum neurotoxin A (BoNT/A) belongs to the most dangerous class of bioweapons. Despite this, BoNT/A is used to treat a wide range of common medical conditions such as migraines and a variety of ocular motility and movement disorders. BoNT/A is probably best known for its use as an antiwrinkle agent in cosmetic applications (including Botox and Dysport). BoNT/A application causes long-lasting flaccid paralysis of muscles through inhibiting the release of the neurotransmitter acetylcholine by cleaving synaptosomal-associated protein 25 (SNAP-25) within presynaptic nerve terminals. Two types of BoNT/A receptor have been identified, both of which are required for BoNT/A toxicity and are therefore likely to cooperate with each other: gangliosides and members of the synaptic vesicle glycoprotein 2 (SV2) family, which are putative transporter proteins that are predicted to have 12 transmembrane domains, associate with the receptor-binding domain of the toxin. Recently, fibroblast growth factor receptor 3 (FGFR3) has also been reported to be a potential BoNT/A receptor. In SV2 proteins, the BoNT/A-binding site has been mapped to the luminal domain, but the molecular details of the interaction between BoNT/A and SV2 are unknown. Here we determined the high-resolution crystal structure of the BoNT/A receptor-binding domain (BoNT/A-RBD) in complex with the SV2C luminal domain (SV2C-LD). SV2C-LD consists of a right-handed, quadrilateral beta-helix that associates with BoNT/A-RBD mainly through backbone-to-backbone interactions at open beta-strand edges, in a manner that resembles the inter-strand interactions in amyloid structures. Competition experiments identified a peptide that inhibits the formation of the complex. Our findings provide a strong platform for the development of novel antitoxin agents and for the rational design of BoNT/A variants with improved therapeutic properties.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Benoit, Roger M -- Frey, Daniel -- Hilbert, Manuel -- Kevenaar, Josta T -- Wieser, Mara M -- Stirnimann, Christian U -- McMillan, David -- Ceska, Tom -- Lebon, Florence -- Jaussi, Rolf -- Steinmetz, Michel O -- Schertler, Gebhard F X -- Hoogenraad, Casper C -- Capitani, Guido -- Kammerer, Richard A -- England -- Nature. 2014 Jan 2;505(7481):108-11. doi: 10.1038/nature12732. Epub 2013 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland. ; 1] Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland [2]. ; 1] Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands [2]. ; Swiss Light Source, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland. ; UCB Celltech, UCB Pharma, UCB NewMedicines, Slough SL1 4EN, UK. ; UCB Pharma, UCB NewMedicines, B-1420 Braine-L'Alleud, Belgium. ; 1] Laboratory of Biomolecular Research, Paul Scherrer Institut, CH-5232 Villigen PSI, Switzerland [2] Department of Biology, ETH Zurich, CH-8093 Zurich, Switzerland. ; Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24240280" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Botulinum Toxins, Type A/*chemistry/*metabolism ; Crystallography, X-Ray ; Endocytosis/drug effects ; HEK293 Cells ; Humans ; Membrane Glycoproteins/*chemistry/*metabolism ; Models, Molecular ; Neostriatum/cytology ; Nerve Tissue Proteins/*chemistry/*metabolism ; Neurons/drug effects ; Peptide Fragments/chemistry/pharmacology ; Structure-Activity Relationship
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    Megadata: The odd couple (2013)
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    Publication Date: 2013-01-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vance, Erik -- England -- Nature. 2012 Nov 22;491(7425):S52-4.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23320285" target="_blank"〉PubMed〈/a〉
    Keywords: Biomarkers, Tumor/analysis ; Biomedical Research/*methods ; Computer Simulation ; *Data Mining ; Humans ; *Interdisciplinary Studies ; Models, Biological ; Neoplasm Proteins/genetics/metabolism ; *Neoplasms/diagnosis/drug therapy/mortality/pathology ; Precision Medicine ; Proteome/genetics/metabolism ; *Proteomics/methods ; United States
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    Activation and allosteric modulation of a muscarinic acetylcholine receptor (2013)
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    Publication Date: 2013-11-22
    Description: Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the beta2 adrenergic receptor (beta2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the beta2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020789/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020789/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kruse, Andrew C -- Ring, Aaron M -- Manglik, Aashish -- Hu, Jianxin -- Hu, Kelly -- Eitel, Katrin -- Hubner, Harald -- Pardon, Els -- Valant, Celine -- Sexton, Patrick M -- Christopoulos, Arthur -- Felder, Christian C -- Gmeiner, Peter -- Steyaert, Jan -- Weis, William I -- Garcia, K Christopher -- Wess, Jurgen -- Kobilka, Brian K -- GM08311806/GM/NIGMS NIH HHS/ -- NS02847123/NS/NINDS NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- U19 GM106990/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Dec 5;504(7478):101-6. doi: 10.1038/nature12735. Epub 2013 Nov 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24256733" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Binding Sites ; Cytoplasm/metabolism ; Humans ; Isoxazoles/chemistry/metabolism ; *Models, Molecular ; Protein Binding ; Protein Structure, Tertiary ; Quaternary Ammonium Compounds/chemistry/metabolism ; Receptors, Muscarinic/*chemistry/*metabolism
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    alphaTAT1 catalyses microtubule acetylation at clathrin-coated pits (2013)
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    Publication Date: 2013-10-08
    Description: In most eukaryotic cells microtubules undergo post-translational modifications such as acetylation of alpha-tubulin on lysine 40, a widespread modification restricted to a subset of microtubules that turns over slowly. This subset of stable microtubules accumulates in cell protrusions and regulates cell polarization, migration and invasion. However, mechanisms restricting acetylation to these microtubules are unknown. Here we report that clathrin-coated pits (CCPs) control microtubule acetylation through a direct interaction of the alpha-tubulin acetyltransferase alphaTAT1 (refs 8, 9) with the clathrin adaptor AP2. We observe that about one-third of growing microtubule ends contact and pause at CCPs and that loss of CCPs decreases lysine 40 acetylation levels. We show that alphaTAT1 localizes to CCPs through a direct interaction with AP2 that is required for microtubule acetylation. In migrating cells, the polarized orientation of acetylated microtubules correlates with CCP accumulation at the leading edge, and interaction of alphaTAT1 with AP2 is required for directional migration. We conclude that microtubules contacting CCPs become acetylated by alphaTAT1. In migrating cells, this mechanism ensures the acetylation of microtubules oriented towards the leading edge, thus promoting directional cell locomotion and chemotaxis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970258/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970258/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Montagnac, Guillaume -- Meas-Yedid, Vannary -- Irondelle, Marie -- Castro-Castro, Antonio -- Franco, Michel -- Shida, Toshinobu -- Nachury, Maxence V -- Benmerah, Alexandre -- Olivo-Marin, Jean-Christophe -- Chavrier, Philippe -- R01 GM089933/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Oct 24;502(7472):567-70. doi: 10.1038/nature12571. Epub 2013 Oct 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institut Curie, Research Center, 75005 Paris, France [2] Membrane and Cytoskeleton Dynamics, CNRS UMR 144, 75005 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24097348" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Acetyltransferases/*metabolism ; Adaptor Protein Complex 2/metabolism ; Biocatalysis ; Cell Movement ; Clathrin/*metabolism ; Coated Pits, Cell-Membrane/enzymology/*metabolism ; HeLa Cells ; Humans ; Microtubules/chemistry/*metabolism ; Protein Binding ; Tubulin/metabolism
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    The structural mechanism of KCNH-channel regulation by the eag domain (2013)
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    Publication Date: 2013-08-27
    Description: The KCNH voltage-dependent potassium channels (ether-a-go-go, EAG; EAG-related gene, ERG; EAG-like channels, ELK) are important regulators of cellular excitability and have key roles in diseases such as cardiac long QT syndrome type 2 (LQT2), epilepsy, schizophrenia and cancer. The intracellular domains of KCNH channels are structurally distinct from other voltage-gated channels. The amino-terminal region contains an eag domain, which is composed of a Per-Arnt-Sim (PAS) domain and a PAS-cap domain, whereas the carboxy-terminal region contains a cyclic nucleotide-binding homology domain (CNBHD), which is connected to the pore through a C-linker domain. Many disease-causing mutations localize to these specialized intracellular domains, which underlie the unique gating and regulation of KCNH channels. It has been suggested that the eag domain may regulate the channel by interacting with either the S4-S5 linker or the CNBHD. Here we present a 2 A resolution crystal structure of the eag domain-CNBHD complex of the mouse EAG1 (also known as KCNH1) channel. It displays extensive interactions between the eag domain and the CNBHD, indicating that the regulatory mechanism of the eag domain primarily involves the CNBHD. Notably, the structure reveals that a number of LQT2 mutations at homologous positions in human ERG, in addition to cancer-associated mutations in EAG channels, localize to the eag domain-CNBHD interface. Furthermore, mutations at the interface produced marked effects on channel gating, demonstrating the important physiological role of the eag domain-CNBHD interaction. Our structure of the eag domain-CNBHD complex of mouse EAG1 provides unique insights into the physiological and pathophysiological mechanisms of KCNH channels.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910112/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910112/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haitin, Yoni -- Carlson, Anne E -- Zagotta, William N -- F32 HL095241/HL/NHLBI NIH HHS/ -- R01 EY010329/EY/NEI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Sep 19;501(7467):444-8. doi: 10.1038/nature12487. Epub 2013 Aug 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23975098" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; Ether-A-Go-Go Potassium Channels/*chemistry/genetics/*metabolism ; Humans ; Mice ; Models, Molecular ; Nucleotides, Cyclic/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Static Electricity
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    Structural insight into magnetochrome-mediated magnetite biomineralization (2013)
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    Publication Date: 2013-10-08
    Description: Magnetotactic bacteria align along the Earth's magnetic field using an organelle called the magnetosome, a biomineralized magnetite (Fe(II)Fe(III)2O4) or greigite (Fe(II)Fe(III)2S4) crystal embedded in a lipid vesicle. Although the need for both iron(II) and iron(III) is clear, little is known about the biological mechanisms controlling their ratio. Here we present the structure of the magnetosome-associated protein MamP and find that it is built on a unique arrangement of a self-plugged PDZ domain fused to two magnetochrome domains, defining a new class of c-type cytochrome exclusively found in magnetotactic bacteria. Mutational analysis, enzyme kinetics, co-crystallization with iron(II) and an in vitro MamP-assisted magnetite production assay establish MamP as an iron oxidase that contributes to the formation of iron(III) ferrihydrite eventually required for magnetite crystal growth in vivo. These results demonstrate the molecular mechanisms of iron management taking place inside the magnetosome and highlight the role of magnetochrome in iron biomineralization.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Siponen, Marina I -- Legrand, Pierre -- Widdrat, Marc -- Jones, Stephanie R -- Zhang, Wei-Jia -- Chang, Michelle C Y -- Faivre, Damien -- Arnoux, Pascal -- Pignol, David -- T32 GM066698/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Oct 31;502(7473):681-4. doi: 10.1038/nature12573. Epub 2013 Oct 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Commissariat a l'Energie Atomique et aux Energies Alternatives, Direction des Sciences du Vivant, Institut de Biologie Environnementale et de Biotechnologies,, F-13108, France [2] Centre National de la Recherche Scientifique, Unite Mixte de Recherche Biologie Vegetale et Microbiologie Environnementales, Saint-Paul-lez-Durance, F-13108, France [3] Aix-Marseille Universite, Saint-Paul-lez-Durance, F-13108, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24097349" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteria/*cytology/enzymology/genetics/*metabolism ; Bacterial Proteins/chemistry/genetics/metabolism ; Conserved Sequence ; Ferric Compounds/metabolism ; Ferrosoferric Oxide/*metabolism ; Genes, Bacterial/genetics ; Iron/metabolism ; Magnetosomes/*metabolism ; Models, Molecular ; Oxidation-Reduction ; Oxidoreductases/chemistry/genetics/metabolism ; Protein Multimerization ; Protein Structure, Tertiary ; Static Electricity
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    Structure of the human glucagon class B G-protein-coupled receptor (2013)
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    Publication Date: 2013-07-19
    Description: Binding of the glucagon peptide to the glucagon receptor (GCGR) triggers the release of glucose from the liver during fasting; thus GCGR plays an important role in glucose homeostasis. Here we report the crystal structure of the seven transmembrane helical domain of human GCGR at 3.4 A resolution, complemented by extensive site-specific mutagenesis, and a hybrid model of glucagon bound to GCGR to understand the molecular recognition of the receptor for its native ligand. Beyond the shared seven transmembrane fold, the GCGR transmembrane domain deviates from class A G-protein-coupled receptors with a large ligand-binding pocket and the first transmembrane helix having a 'stalk' region that extends three alpha-helical turns above the plane of the membrane. The stalk positions the extracellular domain (~12 kilodaltons) relative to the membrane to form the glucagon-binding site that captures the peptide and facilitates the insertion of glucagon's amino terminus into the seven transmembrane domain.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820480/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820480/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Siu, Fai Yiu -- He, Min -- de Graaf, Chris -- Han, Gye Won -- Yang, Dehua -- Zhang, Zhiyun -- Zhou, Caihong -- Xu, Qingping -- Wacker, Daniel -- Joseph, Jeremiah S -- Liu, Wei -- Lau, Jesper -- Cherezov, Vadim -- Katritch, Vsevolod -- Wang, Ming-Wei -- Stevens, Raymond C -- F32 DK088392/DK/NIDDK NIH HHS/ -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50GM073197/GM/NIGMS NIH HHS/ -- U54 GM094586/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jul 25;499(7459):444-9. doi: 10.1038/nature12393. Epub 2013 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23863937" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Glucagon/chemistry/metabolism ; Humans ; Ligands ; Models, Molecular ; Molecular Sequence Data ; Mutagenesis, Site-Directed ; Protein Binding ; Protein Structure, Tertiary ; Receptors, CXCR4/chemistry/classification ; Receptors, Glucagon/*chemistry/*classification/genetics/metabolism
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    Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication (2013)
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    Publication Date: 2013-09-10
    Description: Faithful propagation of DNA methylation patterns during DNA replication is critical for maintaining cellular phenotypes of individual differentiated cells. Although it is well established that Uhrf1 (ubiquitin-like with PHD and ring finger domains 1; also known as Np95 and ICBP90) specifically binds to hemi-methylated DNA through its SRA (SET and RING finger associated) domain and has an essential role in maintenance of DNA methylation by recruiting Dnmt1 to hemi-methylated DNA sites, the mechanism by which Uhrf1 coordinates the maintenance of DNA methylation and DNA replication is largely unknown. Here we show that Uhrf1-dependent histone H3 ubiquitylation has a prerequisite role in the maintenance DNA methylation. Using Xenopus egg extracts, we successfully reproduce maintenance DNA methylation in vitro. Dnmt1 depletion results in a marked accumulation of Uhrf1-dependent ubiquitylation of histone H3 at lysine 23. Dnmt1 preferentially associates with ubiquitylated H3 in vitro though a region previously identified as a replication foci targeting sequence. The RING finger mutant of Uhrf1 fails to recruit Dnmt1 to DNA replication sites and maintain DNA methylation in mammalian cultured cells. Our findings represent the first evidence, to our knowledge, of the mechanistic link between DNA methylation and DNA replication through histone H3 ubiquitylation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nishiyama, Atsuya -- Yamaguchi, Luna -- Sharif, Jafar -- Johmura, Yoshikazu -- Kawamura, Takeshi -- Nakanishi, Keiko -- Shimamura, Shintaro -- Arita, Kyohei -- Kodama, Tatsuhiko -- Ishikawa, Fuyuki -- Koseki, Haruhiko -- Nakanishi, Makoto -- England -- Nature. 2013 Oct 10;502(7470):249-53. doi: 10.1038/nature12488. Epub 2013 Sep 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan. anishiya@med.nagoya-cu.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24013172" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; DNA Methylation/genetics/*physiology ; DNA Replication/genetics/*physiology ; HEK293 Cells ; HeLa Cells ; Histones/*metabolism ; Humans ; Mice ; Ovum/chemistry ; Protein Binding ; Ubiquitin-Protein Ligases/genetics/*metabolism ; Ubiquitination ; Xenopus Proteins/genetics/*metabolism ; Xenopus laevis/*genetics/*metabolism
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    Crystal structure of a folate energy-coupling factor transporter from Lactobacillus brevis (2013)
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    Publication Date: 2013-04-16
    Description: ATP-binding cassette (ABC) transporters, composed of importers and exporters, form one of the biggest protein superfamilies that transport a variety of substrates across the membrane, powered by ATP hydrolysis. Most ABC transporters are composed of two transmembrane domains and two cytoplasmic nucleotide-binding domains. Also, importers from prokaryotes usually have extra solute-binding proteins in the periplasm that are responsible for the binding of substrates. Structures of importers have been reported that suggested a two-state model for the transport mechanism. Energy-coupling factor (ECF) transporters belong to a new class of ATP-binding cassette importers. Each ECF transporter comprises an energy-coupling module consisting of a transmembrane T protein (EcfT), two nucleotide-binding proteins (EcfA and EcfA'), and another transmembrane substrate-specific binding S protein (EcfS). Despite the similarities with ABC transporters, ECF transporters have different organizational and functional properties. The lack of solute-binding proteins in ECF transporters differentiates them clearly from the canonical ABC importers. Previously reported structures of the EcfS proteins RibU and ThiT clearly demonstrated the binding site of substrate riboflavin and thiamine, respectively. However, the organization of the four different components and the transport mechanism of ECF transporters remain unknown. Here we present the structure of an intact folate ECF transporter from Lactobacillus brevis at a resolution of 3 A. This structure was captured in an inward-facing, nucleotide-free conformation with no bound substrate. The folate-binding protein FolT is nearly parallel to the membrane and is bound almost entirely by EcfT, which adopts an L shape and connects to EcfA and EcfA' through two coupling helices. Two conserved XRX motifs from the coupling helices of EcfT have a vital role in energy coupling by docking into EcfA-EcfA'. We propose a transport model that involves a substantial conformational change of FolT.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Ke -- Zhang, Minhua -- Zhao, Qin -- Yu, Fang -- Guo, Hui -- Wang, Chengyuan -- He, Fangyuan -- Ding, Jianping -- Zhang, Peng -- England -- Nature. 2013 May 9;497(7448):268-71. doi: 10.1038/nature12046. Epub 2013 Apr 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Key Laboratory of Plant Molecular Genetics, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 300 Fenglin Road, Shanghai 200032, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23584589" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/chemistry ; Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/metabolism ; Amino Acid Motifs ; Bacterial Proteins/*chemistry/metabolism ; Conserved Sequence ; Crystallography, X-Ray ; Folic Acid Transporters/*chemistry/metabolism ; Lactobacillus brevis/*chemistry ; Models, Molecular ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Proteolipids/metabolism
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    Structural basis for the inhibition of bacterial multidrug exporters (2013)
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    Publication Date: 2013-07-03
    Description: The multidrug efflux transporter AcrB and its homologues are important in the multidrug resistance of Gram-negative pathogens. However, despite efforts to develop efflux inhibitors, clinically useful inhibitors are not available at present. Pyridopyrimidine derivatives are AcrB- and MexB-specific inhibitors that do not inhibit MexY; MexB and MexY are principal multidrug exporters in Pseudomonas aeruginosa. We have previously determined the crystal structure of AcrB in the absence and presence of antibiotics. Drugs were shown to be exported by a functionally rotating mechanism through tandem proximal and distal multisite drug-binding pockets. Here we describe the first inhibitor-bound structures of AcrB and MexB, in which these proteins are bound by a pyridopyrimidine derivative. The pyridopyrimidine derivative binds tightly to a narrow pit composed of a phenylalanine cluster located in the distal pocket and sterically hinders the functional rotation. This pit is a hydrophobic trap that branches off from the substrate-translocation channel. Phe 178 is located at the edge of this trap in AcrB and MexB and contributes to the tight binding of the inhibitor molecule through a pi-pi interaction with the pyridopyrimidine ring. The voluminous side chain of Trp 177 located at the corresponding position in MexY prevents inhibitor binding. The structure of the hydrophobic trap described in this study will contribute to the development of universal inhibitors of MexB and MexY in P. aeruginosa.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakashima, Ryosuke -- Sakurai, Keisuke -- Yamasaki, Seiji -- Hayashi, Katsuhiko -- Nagata, Chikahiro -- Hoshino, Kazuki -- Onodera, Yoshikuni -- Nishino, Kunihiko -- Yamaguchi, Akihito -- England -- Nature. 2013 Aug 1;500(7460):102-6. doi: 10.1038/nature12300. Epub 2013 Jun 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka 567-0047, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23812586" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/chemistry/metabolism/pharmacology ; Bacterial Outer Membrane Proteins/antagonists & inhibitors/*chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Escherichia coli Proteins/antagonists & inhibitors/*chemistry/metabolism ; Hydrophobic and Hydrophilic Interactions ; Membrane Transport Proteins/*chemistry/metabolism ; Models, Molecular ; Multidrug Resistance-Associated Proteins/antagonists & ; inhibitors/*chemistry/metabolism ; Protein Multimerization ; Pseudomonas aeruginosa/*chemistry/*metabolism ; Pyridines/chemistry/metabolism/pharmacology ; Pyrimidines/chemistry/metabolism/pharmacology ; Pyrimidinones/chemistry/metabolism/pharmacology ; Rotation
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    Tension sensing by Aurora B kinase is independent of survivin-based centromere localization (2013)
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    Publication Date: 2013-04-23
    Description: Accurate segregation of the replicated genome requires chromosome biorientation on the spindle. Biorientation is ensured by Aurora B kinase (Ipl1), a member of the four-subunit chromosomal passenger complex (CPC). Localization of the CPC to the inner centromere is central to the current model for how tension ensures chromosome biorientation: kinetochore-spindle attachments that are not under tension remain close to the inner centromere and are destabilized by Aurora B phosphorylation, whereas kinetochores under tension are pulled away from the influence of Aurora B, stabilizing their microtubule attachments. Here we show that an engineered truncation of the Sli15 (known as INCENP in humans) subunit of budding yeast CPC that eliminates association with the inner centromere nevertheless supports proper chromosome segregation during both mitosis and meiosis. Truncated Sli15 suppresses the deletion phenotypes of the inner-centromere-targeting proteins survivin (Bir1), borealin (Nbl1), Bub1 and Sgo1 (ref. 6). Unlike wild-type Sli15, truncated Sli15 localizes to pre-anaphase spindle microtubules. Premature targeting of full-length Sli15 to microtubules by preventing Cdk1 (also known as Cdc28) phosphorylation also suppresses the inviability of Bir1 deletion. These results suggest that activation of Aurora B kinase by clustering either on chromatin or on microtubules is sufficient for chromosome biorientation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644022/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644022/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Campbell, Christopher S -- Desai, Arshad -- GM074215/GM/NIGMS NIH HHS/ -- R01 GM074215/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 May 2;497(7447):118-21. doi: 10.1038/nature12057. Epub 2013 Apr 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23604256" target="_blank"〉PubMed〈/a〉
    Keywords: Aurora Kinase B ; Aurora Kinases ; CDC2 Protein Kinase/antagonists & inhibitors/metabolism ; Carrier Proteins/genetics/metabolism ; Centromere/*metabolism ; Chromatin/metabolism ; Chromosome Segregation ; Intracellular Signaling Peptides and Proteins/*metabolism ; Kinetochores/metabolism ; Meiosis ; Microbial Viability ; Microtubule-Associated Proteins/deficiency/genetics/*metabolism ; Microtubules/metabolism ; Mitosis ; Models, Biological ; Movement ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/*metabolism ; Saccharomyces cerevisiae/*cytology/enzymology/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Sequence Deletion/genetics
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    Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36 (2013)
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    Publication Date: 2013-10-29
    Description: Members of the CD36 superfamily of scavenger receptor proteins are important regulators of lipid metabolism and innate immunity. They recognize normal and modified lipoproteins, as well as pathogen-associated molecular patterns. The family consists of three members: SR-BI (which delivers cholesterol to the liver and steroidogenic organs and is a co-receptor for hepatitis C virus), LIMP-2/LGP85 (which mediates lysosomal delivery of beta-glucocerebrosidase and serves as a receptor for enterovirus 71 and coxsackieviruses) and CD36 (a fatty-acid transporter and receptor for phagocytosis of effete cells and Plasmodium-infected erythrocytes). Notably, CD36 is also a receptor for modified lipoproteins and beta-amyloid, and has been implicated in the pathogenesis of atherosclerosis and of Alzheimer's disease. Despite their prominent roles in health and disease, understanding the function and abnormalities of the CD36 family members has been hampered by the paucity of information about their structure. Here we determine the crystal structure of LIMP-2 and infer, by homology modelling, the structure of SR-BI and CD36. LIMP-2 shows a helical bundle where beta-glucocerebrosidase binds, and where ligands are most likely to bind to SR-BI and CD36. Remarkably, the crystal structure also shows the existence of a large cavity that traverses the entire length of the molecule. Mutagenesis of SR-BI indicates that the cavity serves as a tunnel through which cholesterol(esters) are delivered from the bound lipoprotein to the outer leaflet of the plasma membrane. We provide evidence supporting a model whereby lipidic constituents of the ligands attached to the receptor surface are handed off to the membrane through the tunnel, accounting for the selective lipid transfer characteristic of SR-BI and CD36.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neculai, Dante -- Schwake, Michael -- Ravichandran, Mani -- Zunke, Friederike -- Collins, Richard F -- Peters, Judith -- Neculai, Mirela -- Plumb, Jonathan -- Loppnau, Peter -- Pizarro, Juan Carlos -- Seitova, Alma -- Trimble, William S -- Saftig, Paul -- Grinstein, Sergio -- Dhe-Paganon, Sirano -- MOP-102474/Canadian Institutes of Health Research/Canada -- MOP-126069/Canadian Institutes of Health Research/Canada -- Wellcome Trust/United Kingdom -- England -- Nature. 2013 Dec 5;504(7478):172-6. doi: 10.1038/nature12684. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Biology Program, The Hospital for Sick Children, Toronto M5G 1X8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162852" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD36/*metabolism ; CHO Cells ; Cricetulus ; HeLa Cells ; Humans ; Lysosome-Associated Membrane Glycoproteins/*chemistry/metabolism ; *Models, Molecular ; Protein Binding ; Protein Structure, Tertiary
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    Adrenaline-activated structure of beta2-adrenoceptor stabilized by an engineered nanobody (2013)
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    Publication Date: 2013-09-24
    Description: G-protein-coupled receptors (GPCRs) are integral membrane proteins that have an essential role in human physiology, yet the molecular processes through which they bind to their endogenous agonists and activate effector proteins remain poorly understood. So far, it has not been possible to capture an active-state GPCR bound to its native neurotransmitter. Crystal structures of agonist-bound GPCRs have relied on the use of either exceptionally high-affinity agonists or receptor stabilization by mutagenesis. Many natural agonists such as adrenaline, which activates the beta2-adrenoceptor (beta2AR), bind with relatively low affinity, and they are often chemically unstable. Using directed evolution, we engineered a high-affinity camelid antibody fragment that stabilizes the active state of the beta2AR, and used this to obtain crystal structures of the activated receptor bound to multiple ligands. Here we present structures of the active-state human beta2AR bound to three chemically distinct agonists: the ultrahigh-affinity agonist BI167107, the high-affinity catecholamine agonist hydroxybenzyl isoproterenol, and the low-affinity endogenous agonist adrenaline. The crystal structures reveal a highly conserved overall ligand recognition and activation mode despite diverse ligand chemical structures and affinities that range from 100 nM to approximately 80 pM. Overall, the adrenaline-bound receptor structure is similar to the others, but it has substantial rearrangements in extracellular loop three and the extracellular tip of transmembrane helix 6. These structures also reveal a water-mediated hydrogen bond between two conserved tyrosines, which appears to stabilize the active state of the beta2AR and related GPCRs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822040/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3822040/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ring, Aaron M -- Manglik, Aashish -- Kruse, Andrew C -- Enos, Michael D -- Weis, William I -- Garcia, K Christopher -- Kobilka, Brian K -- GM08311806/GM/NIGMS NIH HHS/ -- NS02847123/NS/NINDS NIH HHS/ -- R01 GM083118/GM/NIGMS NIH HHS/ -- R01 NS028471/NS/NINDS NIH HHS/ -- R37 NS028471/NS/NINDS NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Oct 24;502(7472):575-9. doi: 10.1038/nature12572. Epub 2013 Sep 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular and Cellular Physiology, Stanford University, Stanford, California 94305, USA [2] Department of Structural Biology, Stanford University, Stanford, California 94305, USA [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24056936" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-2 Receptor Agonists/*pharmacology ; Benzoxazines/pharmacology ; Binding Sites/drug effects ; Crystallography, X-Ray ; Directed Molecular Evolution ; Epinephrine/*pharmacology ; Humans ; Hydrogen Bonding/drug effects ; Isoproterenol/analogs & derivatives/pharmacology ; Ligands ; Models, Molecular ; *Protein Engineering ; Protein Stability/drug effects ; Receptors, Adrenergic, beta-2/*chemistry/drug effects/*metabolism ; Single-Chain Antibodies/genetics/*pharmacology ; Tyrosine/chemistry/metabolism ; Water/chemistry/pharmacology
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    RNA polymerase I structure and transcription regulation (2013)
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    Publication Date: 2013-10-25
    Description: Transcription of ribosomal RNA by RNA polymerase (Pol) I initiates ribosome biogenesis and regulates eukaryotic cell growth. The crystal structure of Pol I from the yeast Saccharomyces cerevisiae at 2.8 A resolution reveals all 14 subunits of the 590-kilodalton enzyme, and shows differences to Pol II. An 'expander' element occupies the DNA template site and stabilizes an expanded active centre cleft with an unwound bridge helix. A 'connector' element invades the cleft of an adjacent polymerase and stabilizes an inactive polymerase dimer. The connector and expander must detach during Pol I activation to enable transcription initiation and cleft contraction by convergent movement of the polymerase 'core' and 'shelf' modules. Conversion between an inactive expanded and an active contracted polymerase state may generally underlie transcription. Regulatory factors can modulate the core-shelf interface that includes a 'composite' active site for RNA chain initiation, elongation, proofreading and termination.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Engel, Christoph -- Sainsbury, Sarah -- Cheung, Alan C -- Kostrewa, Dirk -- Cramer, Patrick -- England -- Nature. 2013 Oct 31;502(7473):650-5. doi: 10.1038/nature12712. Epub 2013 Oct 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Center and Department of Biochemistry, Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universitat Munchen, Feodor-Lynen-Str. 25, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24153182" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Crystallography, X-Ray ; *Gene Expression Regulation ; Models, Molecular ; Protein Conformation ; Protein Multimerization ; Protein Subunits/chemistry/metabolism ; RNA Polymerase I/*chemistry/*metabolism ; Saccharomyces cerevisiae/*enzymology ; Transcription Factors, TFII/chemistry/metabolism ; *Transcription, Genetic
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    Memory and modularity in cell-fate decision making (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-11-22
    Description: Genetically identical cells sharing an environment can display markedly different phenotypes. It is often unclear how much of this variation derives from chance, external signals, or attempts by individual cells to exert autonomous phenotypic programs. By observing thousands of cells for hundreds of consecutive generations under constant conditions, we dissect the stochastic decision between a solitary, motile state and a chained, sessile state in Bacillus subtilis. We show that the motile state is 'memoryless', exhibiting no autonomous control over the time spent in the state. In contrast, the time spent as connected chains of cells is tightly controlled, enforcing coordination among related cells in the multicellular state. We show that the three-protein regulatory circuit governing the decision is modular, as initiation and maintenance of chaining are genetically separable functions. As stimulation of the same initiating pathway triggers biofilm formation, we argue that autonomous timing allows a trial commitment to multicellularity that external signals could extend.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019345/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019345/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Norman, Thomas M -- Lord, Nathan D -- Paulsson, Johan -- Losick, Richard -- GM081563/GM/NIGMS NIH HHS/ -- GM18568/GM/NIGMS NIH HHS/ -- R01 GM018568/GM/NIGMS NIH HHS/ -- R01 GM081563/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Nov 28;503(7477):481-6. doi: 10.1038/nature12804. Epub 2013 Nov 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24256735" target="_blank"〉PubMed〈/a〉
    Keywords: Bacillus subtilis/*cytology/genetics/*physiology ; Models, Biological ; Movement ; Phenotype ; Stochastic Processes ; Time Factors
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    Modulation of allostery by protein intrinsic disorder (2013)
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    Publication Date: 2013-06-21
    Description: Allostery is an intrinsic property of many globular proteins and enzymes that is indispensable for cellular regulatory and feedback mechanisms. Recent theoretical and empirical observations indicate that allostery is also manifest in intrinsically disordered proteins, which account for a substantial proportion of the proteome. Many intrinsically disordered proteins are promiscuous binders that interact with multiple partners and frequently function as molecular hubs in protein interaction networks. The adenovirus early region 1A (E1A) oncoprotein is a prime example of a molecular hub intrinsically disordered protein. E1A can induce marked epigenetic reprogramming of the cell within hours after infection, through interactions with a diverse set of partners that include key host regulators such as the general transcriptional coactivator CREB binding protein (CBP), its paralogue p300, and the retinoblastoma protein (pRb; also called RB1). Little is known about the allosteric effects at play in E1A-CBP-pRb interactions, or more generally in hub intrinsically disordered protein interaction networks. Here we used single-molecule fluorescence resonance energy transfer (smFRET) to study coupled binding and folding processes in the ternary E1A system. The low concentrations used in these high-sensitivity experiments proved to be essential for these studies, which are challenging owing to a combination of E1A aggregation propensity and high-affinity binding interactions. Our data revealed that E1A-CBP-pRb interactions have either positive or negative cooperativity, depending on the available E1A interaction sites. This striking cooperativity switch enables fine-tuning of the thermodynamic accessibility of the ternary versus binary E1A complexes, and may permit a context-specific tuning of associated downstream signalling outputs. Such a modulation of allosteric interactions is probably a common mechanism in molecular hub intrinsically disordered protein function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718496/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718496/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ferreon, Allan Chris M -- Ferreon, Josephine C -- Wright, Peter E -- Deniz, Ashok A -- CA96865/CA/NCI NIH HHS/ -- GM066833/GM/NIGMS NIH HHS/ -- R01 CA096865/CA/NCI NIH HHS/ -- R01 GM066833/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jun 20;498(7454):390-4. doi: 10.1038/nature12294.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23783631" target="_blank"〉PubMed〈/a〉
    Keywords: Adenovirus E1A Proteins/*chemistry/*metabolism ; *Allosteric Regulation ; Amino Acid Motifs ; Animals ; Anisotropy ; CREB-Binding Protein/chemistry/metabolism ; Fluorescence Resonance Energy Transfer ; Humans ; Mice ; Models, Molecular ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; Retinoblastoma Protein/chemistry/metabolism ; Thermodynamics ; p300-CBP Transcription Factors/chemistry
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    Structural basis of kynurenine 3-monooxygenase inhibition (2013)
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    Publication Date: 2013-04-12
    Description: Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (that is, kynurenine pathway), leads to amelioration of Huntington's-disease-relevant phenotypes in yeast, fruitfly and mouse models, as well as in a mouse model of Alzheimer's disease. KMO is a flavin adenine dinucleotide (FAD)-dependent monooxygenase and is located in the outer mitochondrial membrane where it converts l-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders, as well as cancer and several peripheral inflammatory conditions. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained unknown. Here we report the first crystal structure of Saccharomyces cerevisiae KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active-site structure, preventing productive binding of the substrate l-kynurenine. Functional assays and targeted mutagenesis reveal that the active-site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO-UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington's, Alzheimer's and Parkinson's diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736096/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736096/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Amaral, Marta -- Levy, Colin -- Heyes, Derren J -- Lafite, Pierre -- Outeiro, Tiago F -- Giorgini, Flaviano -- Leys, David -- Scrutton, Nigel S -- BB/D01963X/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2013 Apr 18;496(7445):382-5. doi: 10.1038/nature12039. Epub 2013 Apr 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23575632" target="_blank"〉PubMed〈/a〉
    Keywords: Arginine/metabolism ; Blood-Brain Barrier/metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Cyclopropanes/*chemistry/*pharmacology ; Drug Design ; Enzyme Inhibitors/*chemistry/*pharmacology ; Humans ; Huntington Disease/drug therapy/enzymology ; Kynurenine/metabolism ; Kynurenine 3-Monooxygenase/*antagonists & inhibitors/*chemistry/metabolism ; Models, Molecular ; Molecular Targeted Therapy ; Protein Conformation ; Reproducibility of Results ; Saccharomyces cerevisiae/*enzymology ; Structure-Activity Relationship
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    The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis (2013)
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    Publication Date: 2013-05-28
    Description: A complex interaction of signalling events, including the Wnt pathway, regulates sprouting of blood vessels from pre-existing vasculature during angiogenesis. Here we show that two distinct mutations in the (uro)chordate-specific gumby (also called Fam105b) gene cause an embryonic angiogenic phenotype in gumby mice. Gumby interacts with disheveled 2 (DVL2), is expressed in canonical Wnt-responsive endothelial cells and encodes an ovarian tumour domain class of deubiquitinase that specifically cleaves linear ubiquitin linkages. A crystal structure of gumby in complex with linear diubiquitin reveals how the identified mutations adversely affect substrate binding and catalytic function in line with the severity of their angiogenic phenotypes. Gumby interacts with HOIP (also called RNF31), a key component of the linear ubiquitin assembly complex, and decreases linear ubiquitination and activation of NF-kappaB-dependent transcription. This work provides support for the biological importance of linear (de)ubiquitination in angiogenesis, craniofacial and neural development and in modulating Wnt signalling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rivkin, Elena -- Almeida, Stephanie M -- Ceccarelli, Derek F -- Juang, Yu-Chi -- MacLean, Teresa A -- Srikumar, Tharan -- Huang, Hao -- Dunham, Wade H -- Fukumura, Ryutaro -- Xie, Gang -- Gondo, Yoichi -- Raught, Brian -- Gingras, Anne-Claude -- Sicheri, Frank -- Cordes, Sabine P -- IHO 94384/Canadian Institutes of Health Research/Canada -- MOP 111199/Canadian Institutes of Health Research/Canada -- MOP 97966/Canadian Institutes of Health Research/Canada -- MOP119289/Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Jun 20;498(7454):318-24. doi: 10.1038/nature12296. Epub 2013 May 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Samuel Lunenfeld Research Institute, Mt Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23708998" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Alleles ; Amino Acid Sequence ; Animals ; Base Sequence ; Crystallography, X-Ray ; Embryo, Mammalian/blood supply/embryology/metabolism ; Endopeptidases/*chemistry/deficiency/genetics/*metabolism ; Female ; Gene Expression Profiling ; HEK293 Cells ; Humans ; Mice ; Models, Molecular ; Molecular Sequence Data ; *Neovascularization, Physiologic/genetics ; Phenotype ; Phosphoproteins/metabolism ; Protein Conformation ; Ubiquitin/*chemistry/*metabolism ; Ubiquitin-Protein Ligases/metabolism ; *Ubiquitination ; Wnt Signaling Pathway
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    Transport dynamics in a glutamate transporter homologue (2013)
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    Publication Date: 2013-06-25
    Description: Glutamate transporters are integral membrane proteins that catalyse neurotransmitter uptake from the synaptic cleft into the cytoplasm of glial cells and neurons. Their mechanism of action involves transitions between extracellular (outward)-facing and intracellular (inward)-facing conformations, whereby substrate binding sites become accessible to either side of the membrane. This process has been proposed to entail transmembrane movements of three discrete transport domains within a trimeric scaffold. Using single-molecule fluorescence resonance energy transfer (smFRET) imaging, we have directly observed large-scale transport domain movements in a bacterial homologue of glutamate transporters. We find that individual transport domains alternate between periods of quiescence and periods of rapid transitions, reminiscent of bursting patterns first recorded in single ion channels using patch-clamp methods. We propose that the switch to the dynamic mode in glutamate transporters is due to separation of the transport domain from the trimeric scaffold, which precedes domain movements across the bilayer. This spontaneous dislodging of the substrate-loaded transport domain is approximately 100-fold slower than subsequent transmembrane movements and may be rate determining in the transport cycle.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829612/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829612/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Akyuz, Nurunisa -- Altman, Roger B -- Blanchard, Scott C -- Boudker, Olga -- 5U54GM087519/GM/NIGMS NIH HHS/ -- R01 NS064357/NS/NINDS NIH HHS/ -- R01NS064357/NS/NINDS NIH HHS/ -- U54 GM087519/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Oct 3;502(7469):114-8. doi: 10.1038/nature12265. Epub 2013 Jun 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10064, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23792560" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Transport System X-AG/*chemistry/genetics/*metabolism ; Aspartic Acid/chemistry ; Biological Transport ; Fluorescence Resonance Energy Transfer ; *Models, Molecular ; Mutation ; Protein Binding ; Protein Structure, Tertiary ; Pyrococcus horikoshii/chemistry/genetics/*metabolism ; Sodium/chemistry
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    A conformational switch in HP1 releases auto-inhibition to drive heterochromatin assembly (2013)
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    Publication Date: 2013-03-15
    Description: A hallmark of histone H3 lysine 9 (H3K9)-methylated heterochromatin, conserved from the fission yeast Schizosaccharomyces pombe to humans, is its ability to spread to adjacent genomic regions. Central to heterochromatin spread is heterochromatin protein 1 (HP1), which recognizes H3K9-methylated chromatin, oligomerizes and forms a versatile platform that participates in diverse nuclear functions, ranging from gene silencing to chromosome segregation. How HP1 proteins assemble on methylated nucleosomal templates and how the HP1-nucleosome complex achieves functional versatility remain poorly understood. Here we show that binding of the key S. pombe HP1 protein, Swi6, to methylated nucleosomes drives a switch from an auto-inhibited state to a spreading-competent state. In the auto-inhibited state, a histone-mimic sequence in one Swi6 monomer blocks methyl-mark recognition by the chromodomain of another monomer. Auto-inhibition is relieved by recognition of two template features, the H3K9 methyl mark and nucleosomal DNA. Cryo-electron-microscopy-based reconstruction of the Swi6-nucleosome complex provides the overall architecture of the spreading-competent state in which two unbound chromodomain sticky ends appear exposed. Disruption of the switch between the auto-inhibited and spreading-competent states disrupts heterochromatin assembly and gene silencing in vivo. These findings are reminiscent of other conditionally activated polymerization processes, such as actin nucleation, and open up a new class of regulatory mechanisms that operate on chromatin in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907283/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907283/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Canzio, Daniele -- Liao, Maofu -- Naber, Nariman -- Pate, Edward -- Larson, Adam -- Wu, Shenping -- Marina, Diana B -- Garcia, Jennifer F -- Madhani, Hiten D -- Cooke, Roger -- Schuck, Peter -- Cheng, Yifan -- Narlikar, Geeta J -- AR053720/AR/NIAMS NIH HHS/ -- R01 AR062279/AR/NIAMS NIH HHS/ -- R01 GM071801/GM/NIGMS NIH HHS/ -- R01GM071801/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Apr 18;496(7445):377-81. doi: 10.1038/nature12032. Epub 2013 Mar 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23485968" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/*antagonists & ; inhibitors/*chemistry/*metabolism/ultrastructure ; Cryoelectron Microscopy ; Gene Silencing ; Heterochromatin/chemistry/*metabolism/ultrastructure ; Histones/chemistry/metabolism ; Methylation ; Models, Molecular ; Molecular Sequence Data ; Nucleosomes/chemistry/genetics/metabolism/ultrastructure ; Protein Structure, Tertiary ; Schizosaccharomyces/genetics/*metabolism ; Schizosaccharomyces pombe Proteins/antagonists & ; inhibitors/*chemistry/*metabolism/ultrastructure ; Xenopus laevis
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    Flavin-mediated dual oxidation controls an enzymatic Favorskii-type rearrangement (2013)
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    Publication Date: 2013-10-29
    Description: Flavoproteins catalyse a diversity of fundamental redox reactions and are one of the most studied enzyme families. As monooxygenases, they are universally thought to control oxygenation by means of a peroxyflavin species that transfers a single atom of molecular oxygen to an organic substrate. Here we report that the bacterial flavoenzyme EncM catalyses the peroxyflavin-independent oxygenation-dehydrogenation dual oxidation of a highly reactive poly(beta-carbonyl). The crystal structure of EncM with bound substrate mimics and isotope labelling studies reveal previously unknown flavin redox biochemistry. We show that EncM maintains an unexpected stable flavin-oxygenating species, proposed to be a flavin-N5-oxide, to promote substrate oxidation and trigger a rare Favorskii-type rearrangement that is central to the biosynthesis of the antibiotic enterocin. This work provides new insight into the fine-tuning of the flavin cofactor in offsetting the innate reactivity of a polyketide substrate to direct its efficient electrocyclization.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844076/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Teufel, Robin -- Miyanaga, Akimasa -- Michaudel, Quentin -- Stull, Frederick -- Louie, Gordon -- Noel, Joseph P -- Baran, Phil S -- Palfey, Bruce -- Moore, Bradley S -- R01 AI047818/AI/NIAID NIH HHS/ -- R01AI47818/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 28;503(7477):552-6. doi: 10.1038/nature12643. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, La Jolla, California 92093, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162851" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/biosynthesis ; Bacterial Proteins/chemistry/*metabolism ; Biocatalysis ; Bridged Compounds/metabolism ; Crystallography, X-Ray ; Cyclization ; Flavins/*metabolism ; Flavoproteins/chemistry/*metabolism ; Isotope Labeling ; Mixed Function Oxygenases/chemistry/*metabolism ; Models, Chemical ; Models, Molecular ; Oxidation-Reduction ; Polyketides/metabolism ; Protein Conformation ; Streptomyces/*enzymology/metabolism ; Substrate Specificity
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    mTOR kinase structure, mechanism and regulation (2013)
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    Publication Date: 2013-05-03
    Description: The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. mTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochemistry shows that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active-site residues and conformational changes that underlie inhibitor potency and specificity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512754/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512754/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Haijuan -- Rudge, Derek G -- Koos, Joseph D -- Vaidialingam, Bhamini -- Yang, Hyo J -- Pavletich, Nikola P -- P30 CA008748/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 May 9;497(7448):217-23. doi: 10.1038/nature12122. Epub 2013 May 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23636326" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/chemistry/metabolism ; Adenosine Triphosphate/chemistry/metabolism ; Catalytic Domain/drug effects ; Crystallography, X-Ray ; Furans/chemistry/pharmacology ; Humans ; Indoles/chemistry/metabolism/pharmacology ; Magnesium/chemistry/metabolism ; Models, Molecular ; Naphthyridines/chemistry/metabolism/pharmacology ; Protein Structure, Tertiary/drug effects ; Purines/chemistry/metabolism/pharmacology ; Pyridines/chemistry/pharmacology ; Pyrimidines/chemistry/pharmacology ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Sirolimus/chemistry/metabolism/pharmacology ; Structure-Activity Relationship ; TOR Serine-Threonine Kinases/antagonists & inhibitors/*chemistry/*metabolism ; Tacrolimus Binding Protein 1A/chemistry/metabolism/pharmacology
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    Control of substrate access to the active site in methane monooxygenase (2013)
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    Publication Date: 2013-02-12
    Description: Methanotrophs consume methane as their major carbon source and have an essential role in the global carbon cycle by limiting escape of this greenhouse gas to the atmosphere. These bacteria oxidize methane to methanol by soluble and particulate methane monooxygenases (MMOs). Soluble MMO contains three protein components, a 251-kilodalton hydroxylase (MMOH), a 38.6-kilodalton reductase (MMOR), and a 15.9-kilodalton regulatory protein (MMOB), required to couple electron consumption with substrate hydroxylation at the catalytic diiron centre of MMOH. Until now, the role of MMOB has remained ambiguous owing to a lack of atomic-level information about the MMOH-MMOB (hereafter termed H-B) complex. Here we remedy this deficiency by providing a crystal structure of H-B, which reveals the manner by which MMOB controls the conformation of residues in MMOH crucial for substrate access to the active site. MMOB docks at the alpha(2)beta(2) interface of alpha(2)beta(2)gamma(2) MMOH, and triggers simultaneous conformational changes in the alpha-subunit that modulate oxygen and methane access as well as proton delivery to the diiron centre. Without such careful control by MMOB of these substrate routes to the diiron active site, the enzyme operates as an NADH oxidase rather than a monooxygenase. Biological catalysis involving small substrates is often accomplished in nature by large proteins and protein complexes. The structure presented in this work provides an elegant example of this principle.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596810/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596810/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Seung Jae -- McCormick, Michael S -- Lippard, Stephen J -- Cho, Uhn-Soo -- GM 32114/GM/NIGMS NIH HHS/ -- R01 GM032134/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Feb 21;494(7437):380-4. doi: 10.1038/nature11880. Epub 2013 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23395959" target="_blank"〉PubMed〈/a〉
    Keywords: Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Iron/metabolism ; Methylococcus capsulatus/*enzymology ; Mixed Function Oxygenases/chemistry/metabolism ; Models, Molecular ; Multienzyme Complexes/*chemistry/*metabolism ; Oxidoreductases/chemistry/metabolism ; Oxygenases/*chemistry/*metabolism ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Structure-Activity Relationship ; Substrate Specificity
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    Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-04-05
    Description: Current human immunodeficiency virus-1 (HIV-1) vaccines elicit strain-specific neutralizing antibodies. However, cross-reactive neutralizing antibodies arise in approximately 20% of HIV-1-infected individuals, and details of their generation could provide a blueprint for effective vaccination. Here we report the isolation, evolution and structure of a broadly neutralizing antibody from an African donor followed from the time of infection. The mature antibody, CH103, neutralized approximately 55% of HIV-1 isolates, and its co-crystal structure with the HIV-1 envelope protein gp120 revealed a new loop-based mechanism of CD4-binding-site recognition. Virus and antibody gene sequencing revealed concomitant virus evolution and antibody maturation. Notably, the unmutated common ancestor of the CH103 lineage avidly bound the transmitted/founder HIV-1 envelope glycoprotein, and evolution of antibody neutralization breadth was preceded by extensive viral diversification in and near the CH103 epitope. These data determine the viral and antibody evolution leading to induction of a lineage of HIV-1 broadly neutralizing antibodies, and provide insights into strategies to elicit similar antibodies by vaccination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637846/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637846/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liao, Hua-Xin -- Lynch, Rebecca -- Zhou, Tongqing -- Gao, Feng -- Alam, S Munir -- Boyd, Scott D -- Fire, Andrew Z -- Roskin, Krishna M -- Schramm, Chaim A -- Zhang, Zhenhai -- Zhu, Jiang -- Shapiro, Lawrence -- NISC Comparative Sequencing Program -- Mullikin, James C -- Gnanakaran, S -- Hraber, Peter -- Wiehe, Kevin -- Kelsoe, Garnett -- Yang, Guang -- Xia, Shi-Mao -- Montefiori, David C -- Parks, Robert -- Lloyd, Krissey E -- Scearce, Richard M -- Soderberg, Kelly A -- Cohen, Myron -- Kamanga, Gift -- Louder, Mark K -- Tran, Lillian M -- Chen, Yue -- Cai, Fangping -- Chen, Sheri -- Moquin, Stephanie -- Du, Xiulian -- Joyce, M Gordon -- Srivatsan, Sanjay -- Zhang, Baoshan -- Zheng, Anqi -- Shaw, George M -- Hahn, Beatrice H -- Kepler, Thomas B -- Korber, Bette T M -- Kwong, Peter D -- Mascola, John R -- Haynes, Barton F -- AI067854/AI/NIAID NIH HHS/ -- AI100645/AI/NIAID NIH HHS/ -- P30 AI050410/AI/NIAID NIH HHS/ -- UM1 AI100645/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Apr 25;496(7446):469-76. doi: 10.1038/nature12053. Epub 2013 Apr 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Duke University Human Vaccine Institute, Departments of Medicine and Immunology, Duke University School of Medicine, Durham, North Carolina 27710, USA. hliao@duke.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23552890" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/immunology ; Africa ; Amino Acid Sequence ; Antibodies, Monoclonal/chemistry/genetics/immunology ; Antibodies, Neutralizing/*chemistry/genetics/*immunology ; Antigens, CD4/chemistry/immunology ; Cell Lineage ; Cells, Cultured ; Clone Cells/cytology ; Cross Reactions/immunology ; Crystallography, X-Ray ; Epitopes/chemistry/immunology ; *Evolution, Molecular ; HIV Antibodies/*chemistry/genetics/*immunology ; HIV Envelope Protein gp120/chemistry/genetics/immunology/metabolism ; HIV-1/*chemistry/classification/*immunology ; Humans ; Models, Molecular ; Molecular Sequence Data ; Mutation ; Neutralization Tests ; Phylogeny ; Protein Structure, Tertiary
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    Unusual architecture of the p7 channel from hepatitis C virus (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-06-07
    Description: The hepatitis C virus (HCV) has developed a small membrane protein, p7, which remarkably can self-assemble into a large channel complex that selectively conducts cations. We wanted to examine the structural solution that the viroporin adopts in order to achieve selective cation conduction, because p7 has no homology with any of the known prokaryotic or eukaryotic channel proteins. The activity of p7 can be inhibited by amantadine and rimantadine, which are potent blockers of the influenza M2 channel and licensed drugs against influenza infections. The adamantane derivatives have been used in HCV clinical trials, but large variation in drug efficacy among the various HCV genotypes has been difficult to explain without detailed molecular structures. Here we determine the structures of this HCV viroporin as well as its drug-binding site using the latest nuclear magnetic resonance (NMR) technologies. The structure exhibits an unusual mode of hexameric assembly, where the individual p7 monomers, i, not only interact with their immediate neighbours, but also reach farther to associate with the i+2 and i+3 monomers, forming a sophisticated, funnel-like architecture. The structure also points to a mechanism of cation selection: an asparagine/histidine ring that constricts the narrow end of the funnel serves as a broad cation selectivity filter, whereas an arginine/lysine ring that defines the wide end of the funnel may selectively allow cation diffusion into the channel. Our functional investigation using whole-cell channel recording shows that these residues are critical for channel activity. NMR measurements of the channel-drug complex revealed six equivalent hydrophobic pockets between the peripheral and pore-forming helices to which amantadine or rimantadine binds, and compound binding specifically to this position may allosterically inhibit cation conduction by preventing the channel from opening. Our data provide a molecular explanation for p7-mediated cation conductance and its inhibition by adamantane derivatives.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725310/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725310/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉OuYang, Bo -- Xie, Shiqi -- Berardi, Marcelo J -- Zhao, Xinhao -- Dev, Jyoti -- Yu, Wenjing -- Sun, Bing -- Chou, James J -- GM094608/GM/NIGMS NIH HHS/ -- U54 GM094608/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jun 27;498(7455):521-5. doi: 10.1038/nature12283. Epub 2013 Jun 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23739335" target="_blank"〉PubMed〈/a〉
    Keywords: Adamantane/analogs & derivatives/chemistry/metabolism/pharmacology ; Binding Sites ; Diffusion ; Hepacivirus/*chemistry ; Microscopy, Electron ; Models, Biological ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Porosity ; Rimantadine/chemistry/metabolism/pharmacology ; Structure-Activity Relationship ; Viral Proteins/antagonists & inhibitors/*chemistry/metabolism/ultrastructure
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    Myc-driven endogenous cell competition in the early mammalian embryo (2013)
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    Publication Date: 2013-07-12
    Description: The epiblast is the mammalian embryonic tissue that contains the pluripotent stem cells that generate the whole embryo. We have established a method for inducing functional genetic mosaics in the mouse. Using this system, here we show that induction of a mosaic imbalance of Myc expression in the epiblast provokes the expansion of cells with higher Myc levels through the apoptotic elimination of cells with lower levels, without disrupting development. In contrast, homogeneous shifts in Myc levels did not affect epiblast cell viability, indicating that the observed competition results from comparison of relative Myc levels between epiblast cells. During normal development we found that Myc levels are intrinsically heterogeneous among epiblast cells, and that endogenous cell competition refines the epiblast cell population through the elimination of cells with low relative Myc levels. These results show that natural cell competition in the early mammalian embryo contributes to the selection of the epiblast cell pool.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Claveria, Cristina -- Giovinazzo, Giovanna -- Sierra, Rocio -- Torres, Miguel -- England -- Nature. 2013 Aug 1;500(7460):39-44. doi: 10.1038/nature12389. Epub 2013 Jul 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departamento de Desarrollo y Reparacion Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares, Madrid E-28029, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23842495" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Cell Proliferation ; Embryo, Mammalian/*cytology/*metabolism ; Embryonic Stem Cells/cytology/metabolism ; Female ; Gene Expression ; Genes, myc ; Germ Layers/*cytology/metabolism ; Male ; Mice ; Models, Biological ; Mosaicism/embryology ; Proto-Oncogene Proteins c-myc/*metabolism
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    Discovery of new enzymes and metabolic pathways by using structure and genome context (2013)
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    Publication Date: 2013-09-24
    Description: Assigning valid functions to proteins identified in genome projects is challenging: overprediction and database annotation errors are the principal concerns. We and others are developing computation-guided strategies for functional discovery with 'metabolite docking' to experimentally derived or homology-based three-dimensional structures. Bacterial metabolic pathways often are encoded by 'genome neighbourhoods' (gene clusters and/or operons), which can provide important clues for functional assignment. We recently demonstrated the synergy of docking and pathway context by 'predicting' the intermediates in the glycolytic pathway in Escherichia coli. Metabolite docking to multiple binding proteins and enzymes in the same pathway increases the reliability of in silico predictions of substrate specificities because the pathway intermediates are structurally similar. Here we report that structure-guided approaches for predicting the substrate specificities of several enzymes encoded by a bacterial gene cluster allowed the correct prediction of the in vitro activity of a structurally characterized enzyme of unknown function (PDB 2PMQ), 2-epimerization of trans-4-hydroxy-L-proline betaine (tHyp-B) and cis-4-hydroxy-D-proline betaine (cHyp-B), and also the correct identification of the catabolic pathway in which Hyp-B 2-epimerase participates. The substrate-liganded pose predicted by virtual library screening (docking) was confirmed experimentally. The enzymatic activities in the predicted pathway were confirmed by in vitro assays and genetic analyses; the intermediates were identified by metabolomics; and repression of the genes encoding the pathway by high salt concentrations was established by transcriptomics, confirming the osmolyte role of tHyp-B. This study establishes the utility of structure-guided functional predictions to enable the discovery of new metabolic pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966649/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966649/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Suwen -- Kumar, Ritesh -- Sakai, Ayano -- Vetting, Matthew W -- Wood, B McKay -- Brown, Shoshana -- Bonanno, Jeffery B -- Hillerich, Brandan S -- Seidel, Ronald D -- Babbitt, Patricia C -- Almo, Steven C -- Sweedler, Jonathan V -- Gerlt, John A -- Cronan, John E -- Jacobson, Matthew P -- 54GM094662/GM/NIGMS NIH HHS/ -- P41 GM103311/GM/NIGMS NIH HHS/ -- P41-GM103311/GM/NIGMS NIH HHS/ -- U54 GM074945/GM/NIGMS NIH HHS/ -- U54 GM093342/GM/NIGMS NIH HHS/ -- U54 GM094662/GM/NIGMS NIH HHS/ -- U54GM074945/GM/NIGMS NIH HHS/ -- U54GM093342/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Oct 31;502(7473):698-702. doi: 10.1038/nature12576. Epub 2013 Sep 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24056934" target="_blank"〉PubMed〈/a〉
    Keywords: *Bacteria/enzymology/genetics/metabolism ; Bacterial Proteins/chemistry/genetics/metabolism ; Enzymes/*chemistry/*genetics/metabolism ; Gene Expression Profiling ; Genes, Bacterial/genetics ; Genome, Bacterial/*genetics ; Glycolysis ; Kinetics ; Metabolic Networks and Pathways/*genetics ; Metabolism ; Metabolomics ; Models, Molecular ; Molecular Sequence Annotation/*methods ; Multigene Family/genetics ; Operon ; *Structural Homology, Protein ; Substrate Specificity
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    Structures of protein-protein complexes involved in electron transfer (2013)
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    Publication Date: 2013-03-29
    Description: Electron transfer reactions are essential for life because they underpin oxidative phosphorylation and photosynthesis, processes leading to the generation of ATP, and are involved in many reactions of intermediary metabolism. Key to these roles is the formation of transient inter-protein electron transfer complexes. The structural basis for the control of specificity between partner proteins is lacking because these weak transient complexes have remained largely intractable for crystallographic studies. Inter-protein electron transfer processes are central to all of the key steps of denitrification, an alternative form of respiration in which bacteria reduce nitrate or nitrite to N2 through the gaseous intermediates nitric oxide (NO) and nitrous oxide (N2O) when oxygen concentrations are limiting. The one-electron reduction of nitrite to NO, a precursor to N2O, is performed by either a haem- or copper-containing nitrite reductase (CuNiR) where they receive an electron from redox partner proteins a cupredoxin or a c-type cytochrome. Here we report the structures of the newly characterized three-domain haem-c-Cu nitrite reductase from Ralstonia pickettii (RpNiR) at 1.01 A resolution and its M92A and P93A mutants. Very high resolution provides the first view of the atomic detail of the interface between the core trimeric cupredoxin structure of CuNiR and the tethered cytochrome c domain that allows the enzyme to function as an effective self-electron transfer system where the donor and acceptor proteins are fused together by genomic acquisition for functional advantage. Comparison of RpNiR with the binary complex of a CuNiR with a donor protein, AxNiR-cytc551 (ref. 6), and mutagenesis studies provide direct evidence for the importance of a hydrogen-bonded water at the interface in electron transfer. The structure also provides an explanation for the preferential binding of nitrite to the reduced copper ion at the active site in RpNiR, in contrast to other CuNiRs where reductive inactivation occurs, preventing substrate binding.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672994/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672994/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Antonyuk, Svetlana V -- Han, Cong -- Eady, Robert R -- Hasnain, S Samar -- 097826/Z/11/Z/Wellcome Trust/United Kingdom -- BB/G005869/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2013 Apr 4;496(7443):123-6. doi: 10.1038/nature11996. Epub 2013 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23535590" target="_blank"〉PubMed〈/a〉
    Keywords: Azurin/chemistry/metabolism ; Catalytic Domain ; Copper/chemistry/metabolism ; Cytochromes c/chemistry/metabolism ; *Electron Transport ; Hydrogen Bonding ; Models, Molecular ; Mutant Proteins/chemistry/genetics/metabolism ; Nitrite Reductases/*chemistry/genetics/*metabolism ; Nitrites/chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Protons ; Ralstonia pickettii/*enzymology ; Water/chemistry/metabolism
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    Crystal structures of the calcium pump and sarcolipin in the Mg2+-bound E1 state (2013)
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    Publication Date: 2013-03-05
    Description: P-type ATPases are ATP-powered ion pumps that establish ion concentration gradients across biological membranes, and are distinct from other ATPases in that the reaction cycle includes an autophosphorylation step. The best studied is Ca(2+)-ATPase from muscle sarcoplasmic reticulum (SERCA1a), a Ca(2+) pump that relaxes muscle cells after contraction, and crystal structures have been determined for most of the reaction intermediates. An important outstanding structure is that of the E1 intermediate, which has empty high-affinity Ca(2+)-binding sites ready to accept new cytosolic Ca(2+). In the absence of Ca(2+) and at pH 7 or higher, the ATPase is predominantly in E1, not in E2 (low affinity for Ca(2+)), and if millimolar Mg(2+) is present, one Mg(2+) is expected to occupy one of the Ca(2+)-binding sites with a millimolar dissociation constant. This Mg(2+) accelerates the reaction cycle, not permitting phosphorylation without Ca(2+) binding. Here we describe the crystal structure of native SERCA1a (from rabbit) in this E1.Mg(2+) state at 3.0 A resolution in addition to crystal structures of SERCA1a in E2 free from exogenous inhibitors, and address the structural basis of the activation signal for phosphoryl transfer. Unexpectedly, sarcolipin, a small regulatory membrane protein of Ca(2+)-ATPase, is bound, stabilizing the E1.Mg(2+) state. Sarcolipin is a close homologue of phospholamban, which is a critical mediator of beta-adrenergic signal in Ca(2+) regulation in heart (for reviews, see, for example, refs 8-10), and seems to play an important role in muscle-based thermogenesis. We also determined the crystal structure of recombinant SERCA1a devoid of sarcolipin, and describe the structural basis of inhibition by sarcolipin/phospholamban. Thus, the crystal structures reported here fill a gap in the structural elucidation of the reaction cycle and provide a solid basis for understanding the physiological regulation of the calcium pump.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Toyoshima, Chikashi -- Iwasawa, Shiho -- Ogawa, Haruo -- Hirata, Ayami -- Tsueda, Junko -- Inesi, Giuseppe -- England -- Nature. 2013 Mar 14;495(7440):260-4. doi: 10.1038/nature11899. Epub 2013 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan. ct@iam.u-tokyo.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23455422" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites/drug effects ; Calcium-Binding Proteins/pharmacology ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Magnesium/chemistry/*metabolism/pharmacology ; Models, Molecular ; Muscle Proteins/*chemistry/*metabolism/pharmacology ; Phosphorylation ; Protein Binding ; Protein Conformation/drug effects ; Proteolipids/*chemistry/*metabolism/pharmacology ; Rabbits ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & ; inhibitors/*chemistry/*metabolism
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    Crystal structure of a eukaryotic phosphate transporter (2013)
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    Publication Date: 2013-04-02
    Description: Phosphate is crucial for structural and metabolic needs, including nucleotide and lipid synthesis, signalling and chemical energy storage. Proton-coupled transporters of the major facilitator superfamily (MFS) are essential for phosphate uptake in plants and fungi, and also have a function in sensing external phosphate levels as transceptors. Here we report the 2.9 A structure of a fungal (Piriformospora indica) high-affinity phosphate transporter, PiPT, in an inward-facing occluded state, with bound phosphate visible in the membrane-buried binding site. The structure indicates both proton and phosphate exit pathways and suggests a modified asymmetrical 'rocker-switch' mechanism of phosphate transport. PiPT is related to several human transporter families, most notably the organic cation and anion transporters of the solute carrier family (SLC22), which are implicated in cancer-drug resistance. We modelled representative cation and anion SLC22 transporters based on the PiPT structure to surmise the structural basis for substrate binding and charge selectivity in this important family. The PiPT structure demonstrates and expands on principles of substrate transport by the MFS transporters and illuminates principles of phosphate uptake in particular.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678552/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3678552/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pedersen, Bjorn P -- Kumar, Hemant -- Waight, Andrew B -- Risenmay, Aaron J -- Roe-Zurz, Zygy -- Chau, Bryant H -- Schlessinger, Avner -- Bonomi, Massimiliano -- Harries, William -- Sali, Andrej -- Johri, Atul K -- Stroud, Robert M -- F32 GM088991/GM/NIGMS NIH HHS/ -- GM073210/GM/NIGMS NIH HHS/ -- GM24485/GM/NIGMS NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- R01 GM024485/GM/NIGMS NIH HHS/ -- R37 GM024485/GM/NIGMS NIH HHS/ -- U01 GM061390/GM/NIGMS NIH HHS/ -- U01 GM61390/GM/NIGMS NIH HHS/ -- U19 GM061390/GM/NIGMS NIH HHS/ -- U54 GM094625/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Apr 25;496(7446):533-6. doi: 10.1038/nature12042. Epub 2013 Mar 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23542591" target="_blank"〉PubMed〈/a〉
    Keywords: Basidiomycota/*chemistry ; Binding Sites ; Crystallography, X-Ray ; Eukaryotic Cells/*chemistry ; Humans ; Models, Biological ; Models, Molecular ; Phosphate Transport Proteins/*chemistry/metabolism ; Phosphates/metabolism ; Protein Conformation ; Protons ; Structure-Activity Relationship
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    Crystal structure of an RNA-bound 11-subunit eukaryotic exosome complex (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-02-05
    Description: The exosome is the major 3'-5' RNA-degradation complex in eukaryotes. The ubiquitous core of the yeast exosome (Exo-10) is formed by nine catalytically inert subunits (Exo-9) and a single active RNase, Rrp44. In the nucleus, the Exo-10 core recruits another nuclease, Rrp6. Here we crystallized an approximately 440-kilodalton complex of Saccharomyces cerevisiae Exo-10 bound to a carboxy-terminal region of Rrp6 and to an RNA duplex with a 3'-overhang of 31 ribonucleotides. The 2.8 A resolution structure shows how RNA is funnelled into the Exo-9 channel in a single-stranded conformation by an unwinding pore. Rrp44 adopts a closed conformation and captures the RNA 3'-end that exits from the side of Exo-9. Exo-9 subunits bind RNA with sequence-unspecific interactions reminiscent of archaeal exosomes. The substrate binding and channelling mechanisms of 3'-5' RNA degradation complexes are conserved in all kingdoms of life.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Makino, Debora Lika -- Baumgartner, Marc -- Conti, Elena -- England -- Nature. 2013 Mar 7;495(7439):70-5. doi: 10.1038/nature11870. Epub 2013 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Cell Biology, MPI for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23376952" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Exosome Multienzyme Ribonuclease Complex/*chemistry/*metabolism ; Models, Molecular ; Protein Subunits/*chemistry/metabolism ; RNA/chemistry/*metabolism ; Saccharomyces cerevisiae/*chemistry/genetics ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism
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    A syringe-like injection mechanism in Photorhabdus luminescens toxins (2013)
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    Publication Date: 2013-03-22
    Description: Photorhabdus luminescens is an insect pathogenic bacterium that is symbiotic with entomopathogenic nematodes. On invasion of insect larvae, P. luminescens is released from the nematodes and kills the insect through the action of a variety of virulence factors including large tripartite ABC-type toxin complexes (Tcs). Tcs are typically composed of TcA, TcB and TcC proteins and are biologically active only when complete. Functioning as ADP-ribosyltransferases, TcC proteins were identified as the actual functional components that induce actin-clustering, defects in phagocytosis and cell death. However, little is known about the translocation of TcC into the cell by the TcA and TcB components. Here we show that TcA in P. luminescens (TcdA1) forms a transmembrane pore and report its structure in the prepore and pore state determined by cryoelectron microscopy. We find that the TcdA1 prepore assembles as a pentamer forming an alpha-helical, vuvuzela-shaped channel less than 1.5 nanometres in diameter surrounded by a large outer shell. Membrane insertion is triggered not only at low pH as expected, but also at high pH, explaining Tc action directly through the midgut of insects. Comparisons with structures of the TcdA1 pore inserted into a membrane and in complex with TcdB2 and TccC3 reveal large conformational changes during membrane insertion, suggesting a novel syringe-like mechanism of protein translocation. Our results demonstrate how ABC-type toxin complexes bridge a membrane to insert their lethal components into the cytoplasm of the host cell. We believe that the proposed mechanism is characteristic of the whole ABC-type toxin family. This explanation of toxin translocation is a step towards understanding the host-pathogen interaction and the complex life cycle of P. luminescens and other pathogens, including human pathogenic bacteria, and serves as a strong foundation for the development of biopesticides.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gatsogiannis, Christos -- Lang, Alexander E -- Meusch, Dominic -- Pfaumann, Vanda -- Hofnagel, Oliver -- Benz, Roland -- Aktories, Klaus -- Raunser, Stefan -- England -- Nature. 2013 Mar 28;495(7442):520-3. doi: 10.1038/nature11987. Epub 2013 Mar 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physical Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23515159" target="_blank"〉PubMed〈/a〉
    Keywords: ADP Ribose Transferases/chemistry/metabolism/ultrastructure ; Animals ; Bacterial Proteins/chemistry/*metabolism/ultrastructure ; Bacterial Toxins/chemistry/*metabolism ; Cell Membrane/metabolism ; Cryoelectron Microscopy ; Cytoplasm/metabolism ; Host-Pathogen Interactions ; Insects/cytology/metabolism/microbiology ; Models, Biological ; Models, Molecular ; Photorhabdus/*metabolism/pathogenicity/ultrastructure ; Pore Forming Cytotoxic Proteins/chemistry/*metabolism/ultrastructure ; Protein Conformation ; Protein Transport
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    Computational design of ligand-binding proteins with high affinity and selectivity (2013)
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    Publication Date: 2013-09-06
    Description: The ability to design proteins with high affinity and selectivity for any given small molecule is a rigorous test of our understanding of the physiochemical principles that govern molecular recognition. Attempts to rationally design ligand-binding proteins have met with little success, however, and the computational design of protein-small-molecule interfaces remains an unsolved problem. Current approaches for designing ligand-binding proteins for medical and biotechnological uses rely on raising antibodies against a target antigen in immunized animals and/or performing laboratory-directed evolution of proteins with an existing low affinity for the desired ligand, neither of which allows complete control over the interactions involved in binding. Here we describe a general computational method for designing pre-organized and shape complementary small-molecule-binding sites, and use it to generate protein binders to the steroid digoxigenin (DIG). Of seventeen experimentally characterized designs, two bind DIG; the model of the higher affinity binder has the most energetically favourable and pre-organized interface in the design set. A comprehensive binding-fitness landscape of this design, generated by library selections and deep sequencing, was used to optimize its binding affinity to a picomolar level, and X-ray co-crystal structures of two variants show atomic-level agreement with the corresponding computational models. The optimized binder is selective for DIG over the related steroids digitoxigenin, progesterone and beta-oestradiol, and this steroid binding preference can be reprogrammed by manipulation of explicitly designed hydrogen-bonding interactions. The computational design method presented here should enable the development of a new generation of biosensors, therapeutics and diagnostics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898436/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898436/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tinberg, Christine E -- Khare, Sagar D -- Dou, Jiayi -- Doyle, Lindsey -- Nelson, Jorgen W -- Schena, Alberto -- Jankowski, Wojciech -- Kalodimos, Charalampos G -- Johnsson, Kai -- Stoddard, Barry L -- Baker, David -- P41 GM103533/GM/NIGMS NIH HHS/ -- R01 GM049857/GM/NIGMS NIH HHS/ -- T32 HG000035/HG/NHGRI NIH HHS/ -- T32 HG00035/HG/NHGRI NIH HHS/ -- England -- Nature. 2013 Sep 12;501(7466):212-6. doi: 10.1038/nature12443. Epub 2013 Sep 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24005320" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Biotechnology ; *Computer Simulation ; Crystallography, X-Ray ; Digoxigenin/chemistry/*metabolism ; *Drug Design ; Estradiol/chemistry/metabolism ; Ligands ; Models, Molecular ; Progesterone/chemistry/metabolism ; Protein Binding ; Proteins/*chemistry/*metabolism ; Reproducibility of Results ; Substrate Specificity
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    Mechanism of farnesylated CAAX protein processing by the intramembrane protease Rce1 (2013)
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    Publication Date: 2013-12-03
    Description: CAAX proteins have essential roles in multiple signalling pathways, controlling processes such as proliferation, differentiation and carcinogenesis. The approximately 120 mammalian CAAX proteins function at cellular membranes and include the Ras superfamily of small GTPases, nuclear lamins, the gamma-subunit of heterotrimeric GTPases, and several protein kinases and phosphatases. The proper localization of CAAX proteins to cell membranes is orchestrated by a series of post-translational modifications of the carboxy-terminal CAAX motifs (where C is cysteine, A is an aliphatic amino acid and X is any amino acid). These reactions involve prenylation of the cysteine residue, cleavage at the AAX tripeptide and methylation of the carboxyl-prenylated cysteine residue. The major CAAX protease activity is mediated by Rce1 (Ras and a-factor converting enzyme 1), an intramembrane protease (IMP) of the endoplasmic reticulum. Information on the architecture and proteolytic mechanism of Rce1 has been lacking. Here we report the crystal structure of a Methanococcus maripaludis homologue of Rce1, whose endopeptidase specificity for farnesylated peptides mimics that of eukaryotic Rce1. Its structure, comprising eight transmembrane alpha-helices, and catalytic site are distinct from those of other IMPs. The catalytic residues are located approximately 10 A into the membrane and are exposed to the cytoplasm and membrane through a conical cavity that accommodates the prenylated CAAX substrate. We propose that the farnesyl lipid binds to a site at the opening of two transmembrane alpha-helices, which results in the scissile bond being positioned adjacent to a glutamate-activated nucleophilic water molecule. This study suggests that Rce1 is the founding member of a novel IMP family, the glutamate IMPs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864837/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864837/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Manolaridis, Ioannis -- Kulkarni, Kiran -- Dodd, Roger B -- Ogasawara, Satoshi -- Zhang, Ziguo -- Bineva, Ganka -- O'Reilly, Nicola -- Hanrahan, Sarah J -- Thompson, Andrew J -- Cronin, Nora -- Iwata, So -- Barford, David -- 100140/Wellcome Trust/United Kingdom -- A2560/Cancer Research UK/United Kingdom -- A7403/Cancer Research UK/United Kingdom -- A8022/Cancer Research UK/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2013 Dec 12;504(7479):301-5. doi: 10.1038/nature12754. Epub 2013 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2]. ; 1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2] [3] Division of Biological Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India (K.K.); Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK (R.B.D.). ; 1] Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2] Division of Biological Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India (K.K.); Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK (R.B.D.). ; 1] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. ; Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. ; Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. ; 1] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [2] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] Department of Life Sciences, Imperial College, London SW7 2AZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24291792" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Archaeal Proteins/chemistry/metabolism ; *Biocatalysis ; Conserved Sequence ; Crystallography, X-Ray ; Cysteine/metabolism ; DNA-Binding Proteins/chemistry/metabolism ; Endopeptidases/chemistry/metabolism ; Endoplasmic Reticulum/enzymology ; Escherichia coli Proteins/chemistry/metabolism ; Glutamic Acid/metabolism ; Humans ; Membrane Proteins/*chemistry/metabolism ; Metalloendopeptidases/chemistry/metabolism ; Methanococcus/*enzymology ; Mice ; Models, Molecular ; Molecular Sequence Data ; Peptide Hydrolases/*chemistry/classification/*metabolism ; *Prenylation ; Protein Structure, Tertiary ; Proto-Oncogene Proteins p21(ras)/chemistry/*metabolism ; Signal Transduction ; Substrate Specificity
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    Cross-neutralization of four paramyxoviruses by a human monoclonal antibody (2013)
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    Publication Date: 2013-08-21
    Description: Broadly neutralizing antibodies reactive against most and even all variants of the same viral species have been described for influenza and HIV-1 (ref. 1). However, whether a neutralizing antibody could have the breadth of range to target different viral species was unknown. Human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV) are common pathogens that cause severe disease in premature newborns, hospitalized children and immune-compromised patients, and play a role in asthma exacerbations. Although antisera generated against either HRSV or HMPV are not cross-neutralizing, we speculated that, because of the repeated exposure to these viruses, cross-neutralizing antibodies may be selected in some individuals. Here we describe a human monoclonal antibody (MPE8) that potently cross-neutralizes HRSV and HMPV as well as two animal paramyxoviruses: bovine RSV (BRSV) and pneumonia virus of mice (PVM). In its germline configuration, MPE8 is HRSV-specific and its breadth is achieved by somatic mutations in the light chain variable region. MPE8 did not result in the selection of viral escape mutants that evaded antibody targeting and showed potent prophylactic efficacy in animal models of HRSV and HMPV infection, as well as prophylactic and therapeutic efficacy in the more relevant model of lethal PVM infection. The core epitope of MPE8 was mapped on two highly conserved anti-parallel beta-strands on the pre-fusion viral F protein, which are rearranged in the post-fusion F protein conformation. Twenty-six out of the thirty HRSV-specific neutralizing antibodies isolated were also found to be specific for the pre-fusion F protein. Taken together, these results indicate that MPE8 might be used for the prophylaxis and therapy of severe HRSV and HMPV infections and identify the pre-fusion F protein as a candidate HRSV vaccine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Corti, Davide -- Bianchi, Siro -- Vanzetta, Fabrizia -- Minola, Andrea -- Perez, Laurent -- Agatic, Gloria -- Guarino, Barbara -- Silacci, Chiara -- Marcandalli, Jessica -- Marsland, Benjamin J -- Piralla, Antonio -- Percivalle, Elena -- Sallusto, Federica -- Baldanti, Fausto -- Lanzavecchia, Antonio -- England -- Nature. 2013 Sep 19;501(7467):439-43. doi: 10.1038/nature12442. Epub 2013 Aug 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Humabs BioMed SA, Via Mirasole 1, 6500 Bellinzona, Switzerland. davide.corti@humabs.ch〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23955151" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antibodies, Monoclonal/chemistry/*immunology/isolation & purification/therapeutic ; use ; Antibodies, Neutralizing/chemistry/*immunology/isolation & ; purification/therapeutic use ; Antibody Specificity/immunology ; Cattle ; Cross Reactions/*immunology ; Epitopes/immunology ; Humans ; Immunoglobulin Light Chains/chemistry/immunology ; Immunoglobulin Variable Region/chemistry/immunology ; Metapneumovirus/immunology ; Mice ; Models, Molecular ; Molecular Sequence Data ; Murine pneumonia virus/immunology ; Paramyxoviridae/*classification/*immunology ; Paramyxoviridae Infections/*immunology/prevention & control/therapy/*virology ; Pneumovirus Infections/immunology/prevention & control/virology ; Respiratory Syncytial Virus Infections/immunology/prevention & ; control/therapy/virology ; Respiratory Syncytial Virus, Bovine/immunology ; Respiratory Syncytial Virus, Human/immunology ; Viral Fusion Proteins/chemistry/immunology ; Viral Vaccines/chemistry/immunology
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    Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling (2013)
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    Publication Date: 2013-05-24
    Description: The KRAS oncogene product is considered a major target in anticancer drug discovery. However, direct interference with KRAS signalling has not yet led to clinically useful drugs. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEdelta, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm. Here we report that interfering with binding of mammalian PDEdelta to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDEdelta interaction that selectively bind to the prenyl-binding pocket of PDEdelta with nanomolar affinity, inhibit oncogenic RAS signalling and suppress in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. Our findings may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zimmermann, Gunther -- Papke, Bjorn -- Ismail, Shehab -- Vartak, Nachiket -- Chandra, Anchal -- Hoffmann, Maike -- Hahn, Stephan A -- Triola, Gemma -- Wittinghofer, Alfred -- Bastiaens, Philippe I H -- Waldmann, Herbert -- England -- Nature. 2013 May 30;497(7451):638-42. doi: 10.1038/nature12205. Epub 2013 May 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Biology, Max Planck Institute of Molecular Physiology, D-44227 Dortmund, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23698361" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/drug therapy/genetics/metabolism ; Animals ; Benzimidazoles/*chemistry/metabolism/*pharmacology/therapeutic use ; Binding Sites ; Carcinoma, Pancreatic Ductal/drug therapy/genetics/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & ; inhibitors/chemistry/*metabolism ; Dogs ; Humans ; Hydrogen Bonding ; MAP Kinase Signaling System/drug effects ; Mice ; Mice, Nude ; Mitogen-Activated Protein Kinases/metabolism ; Models, Molecular ; Molecular Conformation ; Neoplasm Transplantation ; Oncogene Protein p21(ras)/*antagonists & inhibitors/genetics/*metabolism ; Protein Binding/drug effects ; Signal Transduction/*drug effects
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    Structure of active beta-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide (2013)
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    Publication Date: 2013-04-23
    Description: The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second-messenger-generating enzymes and other effectors, GRKs phosphorylate activated receptors, and arrestins subsequently bind phosphorylated receptors and cause receptor desensitization. Arrestins activated by interaction with phosphorylated receptors can also mediate G-protein-independent signalling by serving as adaptors to link receptors to numerous signalling pathways. Despite their central role in regulation and signalling of GPCRs, a structural understanding of beta-arrestin activation and interaction with GPCRs is still lacking. Here we report the crystal structure of beta-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). This peptide has previously been shown to functionally and conformationally activate beta-arrestin-1 (ref. 5). To capture this active conformation, we used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of beta-arrestin-1. The structure of the beta-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in beta-arrestin-1 compared to its inactive conformation. These include rotation of the amino- and carboxy-terminal domains relative to each other, and a major reorientation of the 'lariat loop' implicated in maintaining the inactive state of beta-arrestin-1. These results reveal, at high resolution, a receptor-interacting interface on beta-arrestin, and they indicate a potentially general molecular mechanism for activation of these multifunctional signalling and regulatory proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654799/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654799/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shukla, Arun K -- Manglik, Aashish -- Kruse, Andrew C -- Xiao, Kunhong -- Reis, Rosana I -- Tseng, Wei-Chou -- Staus, Dean P -- Hilger, Daniel -- Uysal, Serdar -- Huang, Li-Yin -- Paduch, Marcin -- Tripathi-Shukla, Prachi -- Koide, Akiko -- Koide, Shohei -- Weis, William I -- Kossiakoff, Anthony A -- Kobilka, Brian K -- Lefkowitz, Robert J -- GM072688/GM/NIGMS NIH HHS/ -- GM087519/GM/NIGMS NIH HHS/ -- HL 075443/HL/NHLBI NIH HHS/ -- HL16037/HL/NHLBI NIH HHS/ -- HL70631/HL/NHLBI NIH HHS/ -- NS028471/NS/NINDS NIH HHS/ -- P41 RR011823/RR/NCRR NIH HHS/ -- R01 HL016037/HL/NHLBI NIH HHS/ -- R01 HL070631/HL/NHLBI NIH HHS/ -- R01 NS028471/NS/NINDS NIH HHS/ -- U01 GM094588/GM/NIGMS NIH HHS/ -- U54 GM074946/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 May 2;497(7447):137-41. doi: 10.1038/nature12120. Epub 2013 Apr 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23604254" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arrestins/*chemistry/immunology/*metabolism ; Crystallography, X-Ray ; Humans ; Immunoglobulin Fab Fragments/chemistry/immunology/metabolism ; Models, Molecular ; Phosphopeptides/*chemistry/*metabolism ; Phosphorylation ; Protein Binding ; Protein Conformation ; Protein Stability ; Rats ; Receptors, Vasopressin/*chemistry ; Rotation
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    Structure of a bacterial energy-coupling factor transporter (2013)
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    Publication Date: 2013-04-16
    Description: The energy-coupling factor (ECF) transporters constitute a novel family of conserved membrane transporters in prokaryotes that have a similar domain organization to the ATP-binding cassette transporters. Each ECF transporter comprises a pair of cytosolic ATPases (the A and A' components, or EcfA and EcfA'), a membrane-embedded substrate-binding protein (the S component, or EcfS) and a transmembrane energy-coupling component (the T component, or EcfT) that links the EcfA-EcfA' subcomplex to EcfS. The structure and transport mechanism of the quaternary ECF transporter remain largely unknown. Here we report the crystal structure of a nucleotide-free ECF transporter from Lactobacillus brevis at a resolution of 3.5 A. The T component has a horseshoe-shaped open architecture, with five alpha-helices as transmembrane segments and two cytoplasmic alpha-helices as coupling modules connecting to the A and A' components. Strikingly, the S component, thought to be specific for hydroxymethyl pyrimidine, lies horizontally along the lipid membrane and is bound exclusively by the five transmembrane segments and the two cytoplasmic helices of the T component. These structural features suggest a plausible working model for the transport cycle of the ECF transporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Tingliang -- Fu, Guobin -- Pan, Xiaojing -- Wu, Jianping -- Gong, Xinqi -- Wang, Jiawei -- Shi, Yigong -- England -- Nature. 2013 May 9;497(7448):272-6. doi: 10.1038/nature12045. Epub 2013 Apr 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ministry of Education Key Laboratory of Protein Science, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23584587" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/chemistry ; Anti-Bacterial Agents ; Bacterial Proteins/*chemistry/metabolism ; Crystallography, X-Ray ; Cytoplasm/chemistry/metabolism ; Lactobacillus brevis/*chemistry ; Models, Biological ; Models, Molecular ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Pyrimidines/chemistry/metabolism ; Structure-Activity Relationship ; Substrate Specificity
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    How insulin engages its primary binding site on the insulin receptor (2013)
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    Publication Date: 2013-01-11
    Description: Insulin receptor signalling has a central role in mammalian biology, regulating cellular metabolism, growth, division, differentiation and survival. Insulin resistance contributes to the pathogenesis of type 2 diabetes mellitus and the onset of Alzheimer's disease; aberrant signalling occurs in diverse cancers, exacerbated by cross-talk with the homologous type 1 insulin-like growth factor receptor (IGF1R). Despite more than three decades of investigation, the three-dimensional structure of the insulin-insulin receptor complex has proved elusive, confounded by the complexity of producing the receptor protein. Here we present the first view, to our knowledge, of the interaction of insulin with its primary binding site on the insulin receptor, on the basis of four crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich-repeat domain (L1) of insulin receptor is seen to be sparse, the hormone instead engaging the insulin receptor carboxy-terminal alpha-chain (alphaCT) segment, which is itself remodelled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The alphaCT segment displaces the B-chain C-terminal beta-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases. We support these findings by photo-crosslinking data that place the suggested interactions into the context of the holoreceptor and by isothermal titration calorimetry data that dissect the hormone-insulin receptor interface. Together, our findings provide an explanation for a wealth of biochemical data from the insulin receptor and IGF1R systems relevant to the design of therapeutic insulin analogues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793637/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793637/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Menting, John G -- Whittaker, Jonathan -- Margetts, Mai B -- Whittaker, Linda J -- Kong, Geoffrey K-W -- Smith, Brian J -- Watson, Christopher J -- Zakova, Lenka -- Kletvikova, Emilia -- Jiracek, Jiri -- Chan, Shu Jin -- Steiner, Donald F -- Dodson, Guy G -- Brzozowski, Andrzej M -- Weiss, Michael A -- Ward, Colin W -- Lawrence, Michael C -- DK13914/DK/NIDDK NIH HHS/ -- DK20595/DK/NIDDK NIH HHS/ -- DK40949/DK/NIDDK NIH HHS/ -- R01 DK040949/DK/NIDDK NIH HHS/ -- UL1 TR000439/TR/NCATS NIH HHS/ -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2013 Jan 10;493(7431):241-5. doi: 10.1038/nature11781.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23302862" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Calorimetry ; Cattle ; Cell Line ; Crystallography, X-Ray ; Humans ; Insulin/*chemistry/*metabolism ; Leucine/metabolism ; Ligands ; Models, Molecular ; Protein Binding ; Protein Structure, Secondary ; Receptor, Insulin/*chemistry/*metabolism ; Reproducibility of Results
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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    The structure of the KtrAB potassium transporter (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-04-20
    Description: In bacteria, archaea, fungi and plants the Trk, Ktr and HKT ion transporters are key components of osmotic regulation, pH homeostasis and resistance to drought and high salinity. These ion transporters are functionally diverse: they can function as Na(+) or K(+) channels and possibly as cation/K(+) symporters. They are closely related to potassium channels both at the level of the membrane protein and at the level of the cytosolic regulatory domains. Here we describe the crystal structure of a Ktr K(+) transporter, the KtrAB complex from Bacillus subtilis. The structure shows the dimeric membrane protein KtrB assembled with a cytosolic octameric KtrA ring bound to ATP, an activating ligand. A comparison between the structure of KtrAB-ATP and the structures of the isolated full-length KtrA protein with ATP or ADP reveals a ligand-dependent conformational change in the octameric ring, raising new ideas about the mechanism of activation in these transporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vieira-Pires, Ricardo S -- Szollosi, Andras -- Morais-Cabral, Joao H -- England -- Nature. 2013 Apr 18;496(7445):323-8. doi: 10.1038/nature12055.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, Porto 4150-180, Portugal.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23598340" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Bacillus subtilis/*chemistry ; Bacterial Proteins/*chemistry/*metabolism ; Cation Transport Proteins/*chemistry/*metabolism ; Crystallography, X-Ray ; Ion Transport ; Models, Biological ; Models, Molecular ; Potassium/*metabolism ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Structure-Activity Relationship
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Structural basis for alternating access of a eukaryotic calcium/proton exchanger (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-05-21
    Description: Eukaryotic Ca(2+) regulation involves sequestration into intracellular organelles, and expeditious Ca(2+) release into the cytosol is a hallmark of key signalling transduction pathways. Bulk removal of Ca(2+) after such signalling events is accomplished by members of the Ca(2+):cation (CaCA) superfamily. The CaCA superfamily includes the Na(+)/Ca(2+) (NCX) and Ca(2+)/H(+) (CAX) antiporters, and in mammals the NCX and related proteins constitute families SLC8 and SLC24, and are responsible for the re-establishment of Ca(2+) resting potential in muscle cells, neuronal signalling and Ca(2+) reabsorption in the kidney. The CAX family members maintain cytosolic Ca(2+) homeostasis in plants and fungi during steep rises in intracellular Ca(2+) due to environmental changes, or following signal transduction caused by events such as hyperosmotic shock, hormone response and response to mating pheromones. The cytosol-facing conformations within the CaCA superfamily are unknown, and the transport mechanism remains speculative. Here we determine a crystal structure of the Saccharomyces cerevisiae vacuolar Ca(2+)/H(+) exchanger (Vcx1) at 2.3 A resolution in a cytosol-facing, substrate-bound conformation. Vcx1 is the first structure, to our knowledge, within the CAX family, and it describes the key cytosol-facing conformation of the CaCA superfamily, providing the structural basis for a novel alternating access mechanism by which the CaCA superfamily performs high-throughput Ca(2+) transport across membranes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702627/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702627/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Waight, Andrew B -- Pedersen, Bjorn Panyella -- Schlessinger, Avner -- Bonomi, Massimiliano -- Chau, Bryant H -- Roe-Zurz, Zygy -- Risenmay, Aaron J -- Sali, Andrej -- Stroud, Robert M -- GM073210/GM/NIGMS NIH HHS/ -- GM24485/GM/NIGMS NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- R01 GM024485/GM/NIGMS NIH HHS/ -- R37 GM024485/GM/NIGMS NIH HHS/ -- T32 GM008284/GM/NIGMS NIH HHS/ -- U01 GM061390/GM/NIGMS NIH HHS/ -- U01 GM61390/GM/NIGMS NIH HHS/ -- U19 GM061390/GM/NIGMS NIH HHS/ -- U54 GM094625/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jul 4;499(7456):107-10. doi: 10.1038/nature12233. Epub 2013 May 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23685453" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Antiporters/*chemistry/*metabolism ; Binding Sites ; Calcium/*metabolism ; Crystallography, X-Ray ; Cytosol/*metabolism ; Ion Transport ; Methanococcus/chemistry ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Protein Folding ; *Protons ; Saccharomyces cerevisiae/*chemistry ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism ; Structure-Activity Relationship
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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