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  • Articles  (208)
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  • 1
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    [Perspective] Molecular sieves for gas separation (2016)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2016-07-08
    Description: Separation and purification are critical industrial processes for separating components of chemical mixtures, and these processes account for about half of industrial energy usage (1). Gas mixtures of compounds with very similar physical properties are particularly difficult to separate. On pages 137 and 141 of this issue, Cadiau et al. (2) and Cui et al. (3), respectively, show that microporous materials can be designed to have high adsorption capacity and selectivity for particular hydrocarbons, enabling energy-efficient separation. Author: Jerry Y. S. Lin
    Keywords: Chemistry
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    [Perspective] How to break down crystalline cellulose (2016)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2016-05-27
    Description: Biomass-degrading microorganisms use lytic polysaccharide monooxygenase (LPMO) enzymes to help digest cellulose, chitin, and starch. By cleaving otherwise inaccessible crystalline cellulose chains, these enzymes provide access to hydrolytic enzymes. LPMOs are of interest to biotechnology because efficient depolymerization of cellulose is a major bottleneck for the production of biologically based chemicals and fuels. On page 1098 of this issue, Kracher et al. (1) compare LPMO-reducing substrates in fungi from different taxonomic groups and lifestyles, based on both biochemical and genomic evidence. The results provide insights into reductive activation of LPMO that are important for developing more efficient industrial enzymes for lignocellulose biorefineries. Author: Angel T. Martínez
    Keywords: Chemistry
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    [Editors' Choice] Engineering open structures using DNA (2016)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2016-03-25
    Description: Author: Marc S. Lavine
    Keywords: Chemistry
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Quantum interference and diradicals [Chemistry] (2016)
    National Academy of Sciences
    Details
    Publication Date: 2016-01-27
    Description: An empirical observation of a relationship between a striking feature of electronic transmission through a π-system, destructive quantum interference (QI), on one hand, and the stability of diradicals on the other, leads to the proof of a general theorem that relates the two. Subject to a number of simplifying assumptions,...
    Keywords: Chemistry
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    Misplaced faith (2015)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2015-06-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Jun 4;522(7554):6. doi: 10.1038/522006a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26040858" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry ; *Public Opinion ; Research Personnel/*ethics/standards ; Retraction of Publication as Topic ; Science/ethics/*standards ; Scientific Misconduct/*statistics & numerical data ; *Trust
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Architecture of the mammalian mechanosensitive Piezo1 channel (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-09-22
    Description: Piezo proteins are evolutionarily conserved and functionally diverse mechanosensitive cation channels. However, the overall structural architecture and gating mechanisms of Piezo channels have remained unknown. Here we determine the cryo-electron microscopy structure of the full-length (2,547 amino acids) mouse Piezo1 (Piezo1) at a resolution of 4.8 A. Piezo1 forms a trimeric propeller-like structure (about 900 kilodalton), with the extracellular domains resembling three distal blades and a central cap. The transmembrane region has 14 apparently resolved segments per subunit. These segments form three peripheral wings and a central pore module that encloses a potential ion-conducting pore. The rather flexible extracellular blade domains are connected to the central intracellular domain by three long beam-like structures. This trimeric architecture suggests that Piezo1 may use its peripheral regions as force sensors to gate the central ion-conducting pore.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ge, Jingpeng -- Li, Wanqiu -- Zhao, Qiancheng -- Li, Ningning -- Chen, Maofei -- Zhi, Peng -- Li, Ruochong -- Gao, Ning -- Xiao, Bailong -- Yang, Maojun -- England -- Nature. 2015 Nov 5;527(7576):64-9. doi: 10.1038/nature15247. Epub 2015 Sep 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences or Medicine, Tsinghua University, Beijing 100084, China. ; Ministry of Education, Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. ; IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26390154" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Membrane/metabolism ; *Cryoelectron Microscopy ; Electric Conductivity ; Ion Channel Gating ; Ion Channels/*chemistry/metabolism/*ultrastructure ; Mice ; Models, Molecular ; Pliability ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Crystal structures of a polypeptide processing and secretion transporter (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-07-24
    Description: Bacteria secrete peptides and proteins to communicate, to poison competitors, and to manipulate host cells. Among the various protein-translocation machineries, the peptidase-containing ATP-binding cassette transporters (PCATs) are appealingly simple. Each PCAT contains two peptidase domains that cleave the secretion signal from the substrate, two transmembrane domains that form a translocation pathway, and two nucleotide-binding domains that hydrolyse ATP. In Gram-positive bacteria, PCATs function both as maturation proteases and exporters for quorum-sensing or antimicrobial polypeptides. In Gram-negative bacteria, PCATs interact with two other membrane proteins to form the type 1 secretion system. Here we present crystal structures of PCAT1 from Clostridium thermocellum in two different conformations. These structures, accompanied by biochemical data, show that the translocation pathway is a large alpha-helical barrel sufficient to accommodate small folded proteins. ATP binding alternates access to the transmembrane pathway and also regulates the protease activity, thereby coupling substrate processing to translocation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, David Yin-wei -- Huang, Shuo -- Chen, Jue -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jul 23;523(7561):425-30. doi: 10.1038/nature14623.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Membrane Biology and Biophysics, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA [2] Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10065, USA. ; 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/26201595" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/*chemistry/metabolism ; Adenosine Triphosphate/deficiency/metabolism ; Clostridium thermocellum/*chemistry ; Crystallography, X-Ray ; Models, Molecular ; Peptides/*metabolism/secretion ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Structure-Activity Relationship
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  • 8
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    The crystallography of correlated disorder (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-05-23
    Description: Classical crystallography can determine structures as complicated as multi-component ribosomal assemblies with atomic resolution, but is inadequate for disordered systems--even those as simple as water ice--that occupy the complex middle ground between liquid-like randomness and crystalline periodic order. Correlated disorder nevertheless has clear crystallographic signatures that map to the type of disorder, irrespective of the underlying physical or chemical interactions and material involved. This mapping hints at a common language for disordered states that will help us to understand, control and exploit the disorder responsible for many interesting physical properties.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Keen, David A -- Goodwin, Andrew L -- England -- Nature. 2015 May 21;521(7552):303-9. doi: 10.1038/nature14453.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉ISIS Facility, Rutherford Appleton Laboratory, Harwell Oxford, Didcot, Oxfordshire OX11 0QX, UK. ; Department of Chemistry, University of Oxford, Inorganic Chemistry Laboratory, South Parks Road, Oxford OX1 3QR, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25993960" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallization ; *Crystallography ; Crystallography, X-Ray ; Electronics ; Ice/analysis ; Magnetic Phenomena ; Proteins/chemistry
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    DNA-dependent formation of transcription factor pairs alters their binding specificity (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-11-10
    Description: Gene expression is regulated by transcription factors (TFs), proteins that recognize short DNA sequence motifs. Such sequences are very common in the human genome, and an important determinant of the specificity of gene expression is the cooperative binding of multiple TFs to closely located motifs. However, interactions between DNA-bound TFs have not been systematically characterized. To identify TF pairs that bind cooperatively to DNA, and to characterize their spacing and orientation preferences, we have performed consecutive affinity-purification systematic evolution of ligands by exponential enrichment (CAP-SELEX) analysis of 9,400 TF-TF-DNA interactions. This analysis revealed 315 TF-TF interactions recognizing 618 heterodimeric motifs, most of which have not been previously described. The observed cooperativity occurred promiscuously between TFs from diverse structural families. Structural analysis of the TF pairs, including a novel crystal structure of MEIS1 and DLX3 bound to their identified recognition site, revealed that the interactions between the TFs were predominantly mediated by DNA. Most TF pair sites identified involved a large overlap between individual TF recognition motifs, and resulted in recognition of composite sites that were markedly different from the individual TF's motifs. Together, our results indicate that the DNA molecule commonly plays an active role in cooperative interactions that define the gene regulatory lexicon.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jolma, Arttu -- Yin, Yimeng -- Nitta, Kazuhiro R -- Dave, Kashyap -- Popov, Alexander -- Taipale, Minna -- Enge, Martin -- Kivioja, Teemu -- Morgunova, Ekaterina -- Taipale, Jussi -- England -- Nature. 2015 Nov 19;527(7578):384-8. doi: 10.1038/nature15518. Epub 2015 Nov 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biosciences and Nutrition, Karolinska Institutet, SE 141 83, Sweden. ; European Synchrotron Radiation Facility, 38043 Grenoble, France. ; Genome-Scale Biology Program, University of Helsinki, P.O. Box 63, FI-00014, Finland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26550823" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Base Sequence ; Binding Sites/genetics ; Crystallography, X-Ray ; DNA/*genetics/*metabolism ; Gene Expression Regulation/genetics ; Humans ; Molecular Sequence Data ; Nucleotide Motifs/genetics ; Reproducibility of Results ; *Substrate Specificity/genetics ; Transcription Factors/*metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
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    Long-sought biological compass discovered (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-11-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cyranoski, David -- England -- Nature. 2015 Nov 19;527(7578):283-4. doi: 10.1038/527283a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26581268" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Migration/physiology ; Animals ; Circadian Rhythm/physiology ; Cryptochromes/metabolism ; Drosophila Proteins/chemistry/*metabolism ; Drosophila melanogaster/*physiology ; *Earth (Planet) ; Humans ; Iron/metabolism ; Iron-Sulfur Proteins/chemistry/*metabolism ; *Magnetic Fields ; Models, Molecular ; Protein Conformation ; Spatial Navigation/*physiology ; Whales/physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 11
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    Agrochemical control of plant water use using engineered abscisic acid receptors (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-02-06
    Description: Rising temperatures and lessening fresh water supplies are threatening agricultural productivity and have motivated efforts to improve plant water use and drought tolerance. During water deficit, plants produce elevated levels of abscisic acid (ABA), which improves water consumption and stress tolerance by controlling guard cell aperture and other protective responses. One attractive strategy for controlling water use is to develop compounds that activate ABA receptors, but agonists approved for use have yet to be developed. In principle, an engineered ABA receptor that can be activated by an existing agrochemical could achieve this goal. Here we describe a variant of the ABA receptor PYRABACTIN RESISTANCE 1 (PYR1) that possesses nanomolar sensitivity to the agrochemical mandipropamid and demonstrate its efficacy for controlling ABA responses and drought tolerance in transgenic plants. Furthermore, crystallographic studies provide a mechanistic basis for its activity and demonstrate the relative ease with which the PYR1 ligand-binding pocket can be altered to accommodate new ligands. Thus, we have successfully repurposed an agrochemical for a new application using receptor engineering. We anticipate that this strategy will be applied to other plant receptors and represents a new avenue for crop improvement.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Sang-Youl -- Peterson, Francis C -- Mosquna, Assaf -- Yao, Jin -- Volkman, Brian F -- Cutler, Sean R -- England -- Nature. 2015 Apr 23;520(7548):545-8. doi: 10.1038/nature14123. Epub 2015 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Plant Cell Biology and Department of Botany and Plant Sciences, University of California, Riverside, California 92521, USA [2] Institute for Integrative Genome Biology, Riverside, California 92521, USA. ; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652827" target="_blank"〉PubMed〈/a〉
    Keywords: Abscisic Acid/*metabolism ; Acclimatization/drug effects ; Agrochemicals/*pharmacology ; Amides/*pharmacology ; Arabidopsis/drug effects/genetics/metabolism ; Arabidopsis Proteins/*genetics/*metabolism ; Binding Sites ; Carboxylic Acids/*pharmacology ; Crystallography, X-Ray ; Droughts ; Genetic Engineering ; Genotype ; Ligands ; Lycopersicon esculentum/drug effects/genetics/metabolism ; Membrane Transport Proteins/*genetics/*metabolism ; Models, Molecular ; Plant Transpiration/drug effects ; Plants/*drug effects/genetics/*metabolism ; Plants, Genetically Modified ; Stress, Physiological/drug effects ; Structure-Activity Relationship ; Water/*metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 12
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    Alexander Rich (1924-2015) (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-05-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schimmel, Paul -- England -- Nature. 2015 May 21;521(7552):291. doi: 10.1038/521291a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Scripps Research Institute in Jupiter, Florida, and La Jolla, California. He was a colleague of Alexander Rich at the Massachusetts Institute of Technology in Cambridge from 1967 onwards.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25993953" target="_blank"〉PubMed〈/a〉
    Keywords: Biotechnology/history ; Collagen/chemistry/history ; Crystallography, X-Ray ; DNA, Z-Form/chemistry/*history ; History, 20th Century ; *Nucleic Acid Conformation ; Peptides/chemistry/history ; Polyribosomes/metabolism ; RNA/chemistry/history ; United States
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 13
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    Structure of the human 80S ribosome (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-04-23
    Description: Ribosomes are translational machineries that catalyse protein synthesis. Ribosome structures from various species are known at the atomic level, but obtaining the structure of the human ribosome has remained a challenge; efforts to address this would be highly relevant with regard to human diseases. Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 A, reaching 2.9 A resolution in the most stable regions. It provides unprecedented insights into ribosomal RNA entities and amino acid side chains, notably of the transfer RNA binding sites and specific molecular interactions with the exit site tRNA. It reveals atomic details of the subunit interface, which is seen to remodel strongly upon rotational movements of the ribosomal subunits. Furthermore, the structure paves the way for analysing antibiotic side effects and diseases associated with deregulated protein synthesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Khatter, Heena -- Myasnikov, Alexander G -- Natchiar, S Kundhavai -- Klaholz, Bruno P -- England -- Nature. 2015 Apr 30;520(7549):640-5. doi: 10.1038/nature14427. Epub 2015 Apr 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, IGBMC (Institute of Genetics and of Molecular and Cellular Biology), 1 rue Laurent Fries, 67404 Illkirch, France [2] Centre National de la Recherche Scientifique (CNRS), UMR 7104, 67404 Illkirch, France [3] Institut National de la Sante et de la Recherche Medicale (INSERM) U964, 67404 Illkirch, France [4] Universite de Strasbourg, 67081 Strasbourg, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25901680" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; *Cryoelectron Microscopy ; Electrons ; Humans ; Models, Molecular ; RNA, Ribosomal/chemistry/metabolism/ultrastructure ; RNA, Transfer/chemistry/metabolism/ultrastructure ; Ribosomal Proteins/chemistry/metabolism/ultrastructure ; Ribosome Subunits/chemistry/metabolism/ultrastructure ; Ribosomes/*chemistry/metabolism/*ultrastructure
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  • 14
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    Two disparate ligand-binding sites in the human P2Y1 receptor (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-03-31
    Description: In response to adenosine 5'-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7 A resolution, and with a non-nucleotide antagonist BPTU at 2.2 A resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y1R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y12R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408927/" 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/PMC4408927/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Dandan -- Gao, Zhan-Guo -- Zhang, Kaihua -- Kiselev, Evgeny -- Crane, Steven -- Wang, Jiang -- Paoletta, Silvia -- Yi, Cuiying -- Ma, Limin -- Zhang, Wenru -- Han, Gye Won -- Liu, Hong -- Cherezov, Vadim -- Katritch, Vsevolod -- Jiang, Hualiang -- Stevens, Raymond C -- Jacobson, Kenneth A -- Zhao, Qiang -- Wu, Beili -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54GM094618/GM/NIGMS NIH HHS/ -- Z01 DK031116-21/Intramural NIH HHS/ -- Z01DK031116-26/DK/NIDDK NIH HHS/ -- ZIA DK031116-26/Intramural NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):317-21. doi: 10.1038/nature14287. Epub 2015 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA. ; Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA. ; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; 1] Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA [2] Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA [3] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25822790" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/analogs & derivatives/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Deoxyadenine Nucleotides/*chemistry/*metabolism/pharmacology ; Humans ; Ligands ; Models, Molecular ; Molecular Conformation ; Purinergic P2Y Receptor Antagonists/*chemistry/metabolism/pharmacology ; Receptors, Purinergic P2Y1/*chemistry/*metabolism ; Thionucleotides/chemistry/metabolism ; Uracil/*analogs & derivatives/chemistry/metabolism/pharmacology
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  • 15
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    Conformational dynamics of a class C G-protein-coupled receptor (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-08-11
    Description: G-protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors in eukaryotes. Crystal structures have provided insight into GPCR interactions with ligands and G proteins, but our understanding of the conformational dynamics of activation is incomplete. Metabotropic glutamate receptors (mGluRs) are dimeric class C GPCRs that modulate neuronal excitability, synaptic plasticity, and serve as drug targets for neurological disorders. A 'clamshell' ligand-binding domain (LBD), which contains the ligand-binding site, is coupled to the transmembrane domain via a cysteine-rich domain, and LBD closure seems to be the first step in activation. Crystal structures of isolated mGluR LBD dimers led to the suggestion that activation also involves a reorientation of the dimer interface from a 'relaxed' to an 'active' state, but the relationship between ligand binding, LBD closure and dimer interface rearrangement in activation remains unclear. Here we use single-molecule fluorescence resonance energy transfer to probe the activation mechanism of full-length mammalian group II mGluRs. We show that the LBDs interconvert between three conformations: resting, activated and a short-lived intermediate state. Orthosteric agonists induce transitions between these conformational states, with efficacy determined by occupancy of the active conformation. Unlike mGluR2, mGluR3 displays basal dynamics, which are Ca(2+)-dependent and lead to basal protein activation. Our results support a general mechanism for the activation of mGluRs in which agonist binding induces closure of the LBDs, followed by dimer interface reorientation. Our experimental strategy should be widely applicable to study conformational dynamics in GPCRs and other membrane proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597782/" 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/PMC4597782/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vafabakhsh, Reza -- Levitz, Joshua -- Isacoff, Ehud Y -- 2PN2EY018241/EY/NEI NIH HHS/ -- PN2 EY018241/EY/NEI NIH HHS/ -- England -- Nature. 2015 Aug 27;524(7566):497-501. doi: 10.1038/nature14679. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. ; Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA. ; Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258295" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Drug Partial Agonism ; *Fluorescence Resonance Energy Transfer ; Humans ; Ligands ; Models, Biological ; Models, Molecular ; Protein Binding ; Protein Conformation ; Rats ; Receptors, Metabotropic Glutamate/*chemistry/*classification/genetics/metabolism
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    Structural basis of JAZ repression of MYC transcription factors in jasmonate signalling (2015)
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    Publication Date: 2015-08-11
    Description: The plant hormone jasmonate plays crucial roles in regulating plant responses to herbivorous insects and microbial pathogens and is an important regulator of plant growth and development. Key mediators of jasmonate signalling include MYC transcription factors, which are repressed by jasmonate ZIM-domain (JAZ) transcriptional repressors in the resting state. In the presence of active jasmonate, JAZ proteins function as jasmonate co-receptors by forming a hormone-dependent complex with COI1, the F-box subunit of an SCF-type ubiquitin E3 ligase. The hormone-dependent formation of the COI1-JAZ co-receptor complex leads to ubiquitination and proteasome-dependent degradation of JAZ repressors and release of MYC proteins from transcriptional repression. The mechanism by which JAZ proteins repress MYC transcription factors and how JAZ proteins switch between the repressor function in the absence of hormone and the co-receptor function in the presence of hormone remain enigmatic. Here we show that Arabidopsis MYC3 undergoes pronounced conformational changes when bound to the conserved Jas motif of the JAZ9 repressor. The Jas motif, previously shown to bind to hormone as a partly unwound helix, forms a complete alpha-helix that displaces the amino (N)-terminal helix of MYC3 and becomes an integral part of the MYC N-terminal fold. In this position, the Jas helix competitively inhibits MYC3 interaction with the MED25 subunit of the transcriptional Mediator complex. Our structural and functional studies elucidate a dynamic molecular switch mechanism that governs the repression and activation of a major plant hormone pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567411/" 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/PMC4567411/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Feng -- Yao, Jian -- Ke, Jiyuan -- Zhang, Li -- Lam, Vinh Q -- Xin, Xiu-Fang -- Zhou, X Edward -- Chen, Jian -- Brunzelle, Joseph -- Griffin, Patrick R -- Zhou, Mingguo -- Xu, H Eric -- Melcher, Karsten -- He, Sheng Yang -- R01 AI068718/AI/NIAID NIH HHS/ -- R01 GM102545/GM/NIGMS NIH HHS/ -- R01AI060761/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 10;525(7568):269-73. doi: 10.1038/nature14661. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Structural Sciences and Laboratory of Structural Biology and Biochemistry, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. ; DOE Plant Research Laboratory, Michigan State University, East Lansing, Michigan 48824, USA. ; College of Plant Protection, Nanjing Agricultural University, No. 1 Weigang, 210095, Nanjing, Jiangsu Province, China. ; Department of Biological Sciences, Western Michigan University, Kalamazoo, Michigan 49008, USA. ; Department of Plant Biology, Michigan State University, East Lansing, Michigan 48824, USA. ; Department of Molecular Therapeutics, Translational Research Institute, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA. ; College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang, China. ; Department of Molecular Pharmacology and Biological Chemistry, Life Sciences Collaborative Access Team, Synchrotron Research Center, Northwestern University, Argonne, Illinois 60439, USA. ; Key Laboratory of Receptor Research, VARI-SIMM Center, Center for Structure and Function of Drug Targets, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. ; Howard Hughes Medical Institute, Michigan State University, East Lansing, Michigan 48824, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258305" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Apoproteins/chemistry/metabolism ; *Arabidopsis/chemistry/metabolism ; Arabidopsis Proteins/*antagonists & inhibitors/*chemistry/genetics/*metabolism ; Binding, Competitive/genetics ; Crystallography, X-Ray ; Cyclopentanes/*metabolism ; Models, Molecular ; Nuclear Proteins/metabolism ; Oxylipins/*metabolism ; Plant Growth Regulators/*metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding/genetics ; Protein Conformation ; Repressor Proteins/*chemistry/genetics/*metabolism ; *Signal Transduction ; Trans-Activators/*antagonists & inhibitors/*chemistry/genetics/metabolism ; Ubiquitination
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    Structure of the TRPA1 ion channel suggests regulatory mechanisms (2015)
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    Publication Date: 2015-04-10
    Description: The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism. These include a broad class of electrophiles that activate the channel through covalent protein modification. TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure. Despite compelling reasons to understand TRPA1 function, structural mechanisms underlying channel regulation remain obscure. Here we use single-particle electron cryo- microscopy to determine the structure of full-length human TRPA1 to approximately 4 A resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features are revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate co-factors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. These findings provide new insights into the mechanisms of TRPA1 regulation, and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409540/" 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/PMC4409540/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paulsen, Candice E -- Armache, Jean-Paul -- Gao, Yuan -- Cheng, Yifan -- Julius, David -- R01 GM098672/GM/NIGMS NIH HHS/ -- R01 NS055299/NS/NINDS NIH HHS/ -- R01GM098672/GM/NIGMS NIH HHS/ -- R01NS055299/NS/NINDS NIH HHS/ -- T32 GM008284/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 23;520(7548):511-7. doi: 10.1038/nature14367. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, University of California, San Francisco, California 94158-2517, USA. ; Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA. ; 1] Department of Physiology, University of California, San Francisco, California 94158-2517, USA [2] Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855297" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Analgesics ; Ankyrin Repeat ; Anti-Inflammatory Agents ; Binding Sites ; Calcium Channels/*chemistry/metabolism/*ultrastructure ; *Cryoelectron Microscopy ; Cytosol/metabolism ; Humans ; Models, Molecular ; Nerve Tissue Proteins/antagonists & ; inhibitors/*chemistry/metabolism/*ultrastructure ; Polyphosphates/metabolism/pharmacology ; Protein Stability/drug effects ; Protein Subunits/chemistry/metabolism ; Structure-Activity Relationship ; Transient Receptor Potential Channels/antagonists & ; inhibitors/*chemistry/metabolism/*ultrastructure
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    Structure of mammalian eIF3 in the context of the 43S preinitiation complex (2015)
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    Publication Date: 2015-09-08
    Description: During eukaryotic translation initiation, 43S complexes, comprising a 40S ribosomal subunit, initiator transfer RNA and initiation factors (eIF) 2, 3, 1 and 1A, attach to the 5'-terminal region of messenger RNA and scan along it to the initiation codon. Scanning on structured mRNAs also requires the DExH-box protein DHX29. Mammalian eIF3 contains 13 subunits and participates in nearly all steps of translation initiation. Eight subunits having PCI (proteasome, COP9 signalosome, eIF3) or MPN (Mpr1, Pad1, amino-terminal) domains constitute the structural core of eIF3, to which five peripheral subunits are flexibly linked. Here we present a cryo-electron microscopy structure of eIF3 in the context of the DHX29-bound 43S complex, showing the PCI/MPN core at approximately 6 A resolution. It reveals the organization of the individual subunits and their interactions with components of the 43S complex. We were able to build near-complete polyalanine-level models of the eIF3 PCI/MPN core and of two peripheral subunits. The implications for understanding mRNA ribosomal attachment and scanning are discussed.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719162/" 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/PMC4719162/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉des Georges, Amedee -- Dhote, Vidya -- Kuhn, Lauriane -- Hellen, Christopher U T -- Pestova, Tatyana V -- Frank, Joachim -- Hashem, Yaser -- R01 GM029169/GM/NIGMS NIH HHS/ -- R01 GM059660/GM/NIGMS NIH HHS/ -- R01 GM29169/GM/NIGMS NIH HHS/ -- R01 GM59660/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 24;525(7570):491-5. doi: 10.1038/nature14891. Epub 2015 Sep 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉HHMI, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA. ; Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York 11203, USA. ; CNRS, Proteomic Platform Strasbourg - Esplanade, Strasbourg 67084, France. ; Department of Biological Sciences, Columbia University, New York, New York 10032, USA. ; CNRS, Architecture et Reactivite de l'ARN, Universite de Strasbourg, Strasbourg 67084, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26344199" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Codon, Initiator/genetics ; Cryoelectron Microscopy ; Eukaryotic Initiation Factor-2/chemistry/metabolism ; Eukaryotic Initiation Factor-3/*chemistry/*metabolism ; Humans ; Models, Molecular ; Multiprotein Complexes/*chemistry/*metabolism ; *Peptide Chain Initiation, Translational ; Peptide Initiation Factors/metabolism ; Protein Structure, Secondary ; Protein Subunits/chemistry/metabolism ; RNA Helicases/chemistry/metabolism ; RNA, Messenger/genetics/metabolism ; RNA, Transfer, Met/metabolism ; Ribosome Subunits, Small, Eukaryotic/chemistry/metabolism ; Ribosomes/*chemistry/*metabolism
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    New cofactor supports alpha,beta-unsaturated acid decarboxylation via 1,3-dipolar cycloaddition (2015)
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    Publication Date: 2015-06-18
    Description: The bacterial ubiD and ubiX or the homologous fungal fdc1 and pad1 genes have been implicated in the non-oxidative reversible decarboxylation of aromatic substrates, and play a pivotal role in bacterial ubiquinone (also known as coenzyme Q) biosynthesis or microbial biodegradation of aromatic compounds, respectively. Despite biochemical studies on individual gene products, the composition and cofactor requirement of the enzyme responsible for in vivo decarboxylase activity remained unclear. Here we show that Fdc1 is solely responsible for the reversible decarboxylase activity, and that it requires a new type of cofactor: a prenylated flavin synthesized by the associated UbiX/Pad1. Atomic resolution crystal structures reveal that two distinct isomers of the oxidized cofactor can be observed, an isoalloxazine N5-iminium adduct and a N5 secondary ketimine species with markedly altered ring structure, both having azomethine ylide character. Substrate binding positions the dipolarophile enoic acid group directly above the azomethine ylide group. The structure of a covalent inhibitor-cofactor adduct suggests that 1,3-dipolar cycloaddition chemistry supports reversible decarboxylation in these enzymes. Although 1,3-dipolar cycloaddition is commonly used in organic chemistry, we propose that this presents the first example, to our knowledge, of an enzymatic 1,3-dipolar cycloaddition reaction. Our model for Fdc1/UbiD catalysis offers new routes in alkene hydrocarbon production or aryl (de)carboxylation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Payne, Karl A P -- White, Mark D -- Fisher, Karl -- Khara, Basile -- Bailey, Samuel S -- Parker, David -- Rattray, Nicholas J W -- Trivedi, Drupad K -- Goodacre, Royston -- Beveridge, Rebecca -- Barran, Perdita -- Rigby, Stephen E J -- Scrutton, Nigel S -- Hay, Sam -- Leys, David -- BB/K017802/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/M/017702/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2015 Jun 25;522(7557):497-501. doi: 10.1038/nature14560. Epub 2015 Jun 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Synthetic Biology of Fine and Speciality Chemicals, Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK. ; Innovation/Biodomain, Shell International Exploration and Production, Westhollow Technology Center, 3333 Highway 6 South, Houston, Texas 77082-3101, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26083754" target="_blank"〉PubMed〈/a〉
    Keywords: Alkenes/chemistry/metabolism ; Aspergillus niger/enzymology/genetics ; *Biocatalysis ; Carboxy-Lyases/chemistry/genetics/*metabolism ; Crystallography, X-Ray ; *Cycloaddition Reaction ; Decarboxylation ; Escherichia coli Proteins/chemistry/genetics/metabolism ; Flavins/biosynthesis/chemistry/metabolism ; Isomerism ; Ligands ; Models, Molecular ; Ubiquinone/biosynthesis
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    Crystal structure of the V(D)J recombinase RAG1-RAG2 (2015)
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    Publication Date: 2015-02-25
    Description: V(D)J recombination in the vertebrate immune system generates a highly diverse population of immunoglobulins and T-cell receptors by combinatorial joining of segments of coding DNA. The RAG1-RAG2 protein complex initiates this site-specific recombination by cutting DNA at specific sites flanking the coding segments. Here we report the crystal structure of the mouse RAG1-RAG2 complex at 3.2 A resolution. The 230-kilodalton RAG1-RAG2 heterotetramer is 'Y-shaped', with the amino-terminal domains of the two RAG1 chains forming an intertwined stalk. Each RAG1-RAG2 heterodimer composes one arm of the 'Y', with the active site in the middle and RAG2 at its tip. The RAG1-RAG2 structure rationalizes more than 60 mutations identified in immunodeficient patients, as well as a large body of genetic and biochemical data. The architectural similarity between RAG1 and the hairpin-forming transposases Hermes and Tn5 suggests the evolutionary conservation of these DNA rearrangements.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342785/" 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/PMC4342785/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Min-Sung -- Lapkouski, Mikalai -- Yang, Wei -- Gellert, Martin -- Z01 DK036147-01/Intramural NIH HHS/ -- Z01 DK036147-02/Intramural NIH HHS/ -- Z01 DK036167-01/Intramural NIH HHS/ -- Z01 DK036167-02/Intramural NIH HHS/ -- ZIA DK036147-03/Intramural NIH HHS/ -- ZIA DK036147-04/Intramural NIH HHS/ -- ZIA DK036147-05/Intramural NIH HHS/ -- ZIA DK036147-06/Intramural NIH HHS/ -- ZIA DK036147-07/Intramural NIH HHS/ -- ZIA DK036147-08/Intramural NIH HHS/ -- ZIA DK036167-03/Intramural NIH HHS/ -- ZIA DK036167-04/Intramural NIH HHS/ -- ZIA DK036167-05/Intramural NIH HHS/ -- ZIA DK036167-06/Intramural NIH HHS/ -- ZIA DK036167-07/Intramural NIH HHS/ -- England -- Nature. 2015 Feb 26;518(7540):507-11. doi: 10.1038/nature14174. Epub 2015 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Biology, NIDDK, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707801" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA-Binding Proteins/*chemistry/genetics/metabolism ; Homeodomain Proteins/*chemistry/genetics/metabolism ; Humans ; Mice ; Models, Molecular ; Mutation/genetics ; Protein Multimerization ; Protein Structure, Quaternary ; Severe Combined Immunodeficiency/genetics ; Transposases/chemistry ; VDJ Recombinases/*chemistry/metabolism ; X-Linked Combined Immunodeficiency Diseases/genetics
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    In situ structures of the segmented genome and RNA polymerase complex inside a dsRNA virus (2015)
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    Publication Date: 2015-10-28
    Description: Viruses in the Reoviridae, like the triple-shelled human rotavirus and the single-shelled insect cytoplasmic polyhedrosis virus (CPV), all package a genome of segmented double-stranded RNAs (dsRNAs) inside the viral capsid and carry out endogenous messenger RNA synthesis through a transcriptional enzyme complex (TEC). By direct electron-counting cryoelectron microscopy and asymmetric reconstruction, we have determined the organization of the dsRNA genome inside quiescent CPV (q-CPV) and the in situ atomic structures of TEC within CPV in both quiescent and transcribing (t-CPV) states. We show that the ten segmented dsRNAs in CPV are organized with ten TECs in a specific, non-symmetric manner, with each dsRNA segment attached directly to a TEC. The TEC consists of two extensively interacting subunits: an RNA-dependent RNA polymerase (RdRP) and an NTPase VP4. We find that the bracelet domain of RdRP undergoes marked conformational change when q-CPV is converted to t-CPV, leading to formation of the RNA template entry channel and access to the polymerase active site. An amino-terminal helix from each of two subunits of the capsid shell protein (CSP) interacts with VP4 and RdRP. These findings establish the link between sensing of environmental cues by the external proteins and activation of endogenous RNA transcription by the TEC inside the virus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Xing -- Ding, Ke -- Yu, Xuekui -- Chang, Winston -- Sun, Jingchen -- Zhou, Z Hong -- 1S10OD018111/OD/NIH HHS/ -- 1S10RR23057/RR/NCRR NIH HHS/ -- AI094386/AI/NIAID NIH HHS/ -- GM071940/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):531-4. doi: 10.1038/nature15767. Epub 2015 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉California Nanosystems Institute, University of California, Los Angeles, California 90095, USA. ; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California 90095, USA. ; Bioengineering, University of California, Los Angeles, California 90095, USA. ; Subtropical Sericulture and Mulberry Resources Protection and Safety Engineering Research Center, Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503045" target="_blank"〉PubMed〈/a〉
    Keywords: Capsid Proteins/chemistry/metabolism/ultrastructure ; Catalytic Domain ; Cryoelectron Microscopy ; *Genome, Viral/genetics ; Models, Molecular ; Multienzyme Complexes/chemistry/metabolism/*ultrastructure ; Nucleoside-Triphosphatase/metabolism/ultrastructure ; Protein Subunits/chemistry/metabolism ; RNA Replicase/chemistry/metabolism/*ultrastructure ; RNA, Double-Stranded/genetics/*ultrastructure ; RNA, Messenger/biosynthesis/genetics/ultrastructure ; RNA, Viral/biosynthesis/genetics/*ultrastructure ; Reoviridae/enzymology/genetics/*ultrastructure ; Templates, Genetic ; Transcription, Genetic
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    Electron cryomicroscopy observation of rotational states in a eukaryotic V-ATPase (2015)
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    Publication Date: 2015-05-15
    Description: Eukaryotic vacuolar H(+)-ATPases (V-ATPases) are rotary enzymes that use energy from hydrolysis of ATP to ADP to pump protons across membranes and control the pH of many intracellular compartments. ATP hydrolysis in the soluble catalytic region of the enzyme is coupled to proton translocation through the membrane-bound region by rotation of a central rotor subcomplex, with peripheral stalks preventing the entire membrane-bound region from turning with the rotor. The eukaryotic V-ATPase is the most complex rotary ATPase: it has three peripheral stalks, a hetero-oligomeric proton-conducting proteolipid ring, several subunits not found in other rotary ATPases, and is regulated by reversible dissociation of its catalytic and proton-conducting regions. Studies of ATP synthases, V-ATPases, and bacterial/archaeal V/A-ATPases have suggested that flexibility is necessary for the catalytic mechanism of rotary ATPases, but the structures of different rotational states have never been observed experimentally. Here we use electron cryomicroscopy to obtain structures for three rotational states of the V-ATPase from the yeast Saccharomyces cerevisiae. The resulting series of structures shows ten proteolipid subunits in the c-ring, setting the ATP:H(+) ratio for proton pumping by the V-ATPase at 3:10, and reveals long and highly tilted transmembrane alpha-helices in the a-subunit that interact with the c-ring. The three different maps reveal the conformational changes that occur to couple rotation in the symmetry-mismatched soluble catalytic region to the membrane-bound proton-translocating region. Almost all of the subunits of the enzyme undergo conformational changes during the transitions between these three rotational states. The structures of these states provide direct evidence that deformation during rotation enables the smooth transmission of power through rotary ATPases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Jianhua -- Benlekbir, Samir -- Rubinstein, John L -- MOP 81294/Canadian Institutes of Health Research/Canada -- England -- Nature. 2015 May 14;521(7551):241-5. doi: 10.1038/nature14365.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Structure and Function Program, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada [2] Department of Medical Biophysics, The University of Toronto, Toronto Medical Discovery Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada. ; Molecular Structure and Function Program, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada. ; 1] Molecular Structure and Function Program, The Hospital for Sick Children Research Institute, 686 Bay Street, Toronto, Ontario M5G 0A4, Canada [2] Department of Medical Biophysics, The University of Toronto, Toronto Medical Discovery Tower, MaRS Centre, 101 College Street, Toronto, Ontario M5G 1L7, Canada [3] Department of Biochemistry, The University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, Ontario M5S 1A8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25971514" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Biocatalysis ; Cell Membrane/chemistry/enzymology/metabolism ; *Cryoelectron Microscopy ; Lipid Bilayers/metabolism ; Models, Molecular ; Pliability ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Protons ; *Rotation ; Saccharomyces cerevisiae/*enzymology ; Solubility ; Vacuolar Proton-Translocating ATPases/*chemistry/metabolism/*ultrastructure
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    Lanosterol reverses protein aggregation in cataracts (2015)
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    Publication Date: 2015-07-23
    Description: The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Ling -- Chen, Xiang-Jun -- Zhu, Jie -- Xi, Yi-Bo -- Yang, Xu -- Hu, Li-Dan -- Ouyang, Hong -- Patel, Sherrina H -- Jin, Xin -- Lin, Danni -- Wu, Frances -- Flagg, Ken -- Cai, Huimin -- Li, Gen -- Cao, Guiqun -- Lin, Ying -- Chen, Daniel -- Wen, Cindy -- Chung, Christopher -- Wang, Yandong -- Qiu, Austin -- Yeh, Emily -- Wang, Wenqiu -- Hu, Xun -- Grob, Seanna -- Abagyan, Ruben -- Su, Zhiguang -- Tjondro, Harry Christianto -- Zhao, Xi-Juan -- Luo, Hongrong -- Hou, Rui -- Perry, J Jefferson P -- Gao, Weiwei -- Kozak, Igor -- Granet, David -- Li, Yingrui -- Sun, Xiaodong -- Wang, Jun -- Zhang, Liangfang -- Liu, Yizhi -- Yan, Yong-Bin -- Zhang, Kang -- England -- Nature. 2015 Jul 30;523(7562):607-11. doi: 10.1038/nature14650. Epub 2015 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; BGI-Shenzhen, Shenzhen 518083, China. ; 1] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [2] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. ; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] CapitalBio Genomics Co., Ltd., Dongguan 523808, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA. ; Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Department of Biochemistry, University of California Riverside, Riverside, California 92521, USA. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA. ; King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia. ; Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [4] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA [5] Veterans Administration Healthcare System, San Diego, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26200341" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Amino Acid Sequence ; Amyloid/chemistry/drug effects/metabolism/ultrastructure ; Animals ; Base Sequence ; Cataract/congenital/*drug therapy/genetics/*metabolism/pathology ; Cell Line ; Child ; Crystallins/chemistry/genetics/metabolism/ultrastructure ; Dogs ; Female ; Humans ; Lanosterol/administration & dosage/*pharmacology/*therapeutic use ; Lens, Crystalline/drug effects/metabolism/pathology ; Male ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry/genetics/metabolism/ultrastructure ; Pedigree ; Protein Aggregates/*drug effects ; Protein Aggregation, Pathological/*drug therapy/pathology
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    Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation (2015)
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    Publication Date: 2015-02-18
    Description: The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30-50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR-ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR-ABL1-driven leukaemia. Axitinib potently inhibited BCR-ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pemovska, Tea -- Johnson, Eric -- Kontro, Mika -- Repasky, Gretchen A -- Chen, Jeffrey -- Wells, Peter -- Cronin, Ciaran N -- McTigue, Michele -- Kallioniemi, Olli -- Porkka, Kimmo -- Murray, Brion W -- Wennerberg, Krister -- England -- Nature. 2015 Mar 5;519(7541):102-5. doi: 10.1038/nature14119. Epub 2015 Feb 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00290 Helsinki, Finland. ; La Jolla Laboratories, Pfizer Worldwide Research &Development, San Diego, California 92121, USA. ; Hematology Research Unit Helsinki, University of Helsinki, and Helsinki University Hospital Comprehensive Cancer Center, Department of Hematology, 00290 Helsinki, Finland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686603" target="_blank"〉PubMed〈/a〉
    Keywords: Angiogenesis Inhibitors/chemistry/pharmacology/therapeutic use ; Cell Line ; Cell Proliferation/drug effects ; Crystallization ; Crystallography, X-Ray ; Drug Repositioning ; Drug Resistance, Neoplasm/genetics ; Drug Screening Assays, Antitumor ; Fusion Proteins, bcr-abl/*antagonists & inhibitors/*chemistry/genetics/metabolism ; Humans ; Imidazoles/*chemistry/*pharmacology/therapeutic use ; Indazoles/*chemistry/*pharmacology/therapeutic use ; Kidney Neoplasms/drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/genetics/metabolism ; Models, Molecular ; Molecular Conformation ; Phosphorylation/drug effects ; Protein Binding ; Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; Proto-Oncogene Proteins c-abl/antagonists & ; inhibitors/chemistry/genetics/metabolism ; Vascular Endothelial Growth Factor Receptor-2/antagonists & ; inhibitors/chemistry/metabolism
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    Mechanistic insights into the recycling machine of the SNARE complex (2015)
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    Publication Date: 2015-01-13
    Description: Evolutionarily conserved SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptors) proteins form a complex that drives membrane fusion in eukaryotes. The ATPase NSF (N-ethylmaleimide sensitive factor), together with SNAPs (soluble NSF attachment protein), disassembles the SNARE complex into its protein components, making individual SNAREs available for subsequent rounds of fusion. Here we report structures of ATP- and ADP-bound NSF, and the NSF/SNAP/SNARE (20S) supercomplex determined by single-particle electron cryomicroscopy at near-atomic to sub-nanometre resolution without imposing symmetry. Large, potentially force-generating, conformational differences exist between ATP- and ADP-bound NSF. The 20S supercomplex exhibits broken symmetry, transitioning from six-fold symmetry of the NSF ATPase domains to pseudo four-fold symmetry of the SNARE complex. SNAPs interact with the SNARE complex with an opposite structural twist, suggesting an unwinding mechanism. The interfaces between NSF, SNAPs, and SNAREs exhibit characteristic electrostatic patterns, suggesting how one NSF/SNAP species can act on many different SNARE complexes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320033/" 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/PMC4320033/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Minglei -- Wu, Shenping -- Zhou, Qiangjun -- Vivona, Sandro -- Cipriano, Daniel J -- Cheng, Yifan -- Brunger, Axel T -- 5-U01AI082051-05/AI/NIAID NIH HHS/ -- P50 GM082250/GM/NIGMS NIH HHS/ -- P50GM082250/GM/NIGMS NIH HHS/ -- R01 GM082893/GM/NIGMS NIH HHS/ -- R01 GM098672/GM/NIGMS NIH HHS/ -- R01GM082893/GM/NIGMS NIH HHS/ -- R01GM098672/GM/NIGMS NIH HHS/ -- R37 MH063105/MH/NIMH NIH HHS/ -- R37MH63105/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Feb 5;518(7537):61-7. doi: 10.1038/nature14148. Epub 2015 Jan 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA. ; Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA. ; 1] Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Department of Structural Biology, Department of Photon Science, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25581794" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Cricetulus ; Cryoelectron Microscopy ; Models, Molecular ; Multiprotein Complexes/*chemistry/*metabolism/ultrastructure ; N-Ethylmaleimide-Sensitive Proteins/chemistry/metabolism/ultrastructure ; Protein Binding ; Protein Structure, Tertiary ; Rats ; SNARE Proteins/*chemistry/*metabolism/ultrastructure ; Soluble N-Ethylmaleimide-Sensitive Factor Attachment ; Proteins/chemistry/metabolism/ultrastructure
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    The inner workings of the hydrazine synthase multiprotein complex (2015)
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    Publication Date: 2015-10-20
    Description: Anaerobic ammonium oxidation (anammox) has a major role in the Earth's nitrogen cycle and is used in energy-efficient wastewater treatment. This bacterial process combines nitrite and ammonium to form dinitrogen (N2) gas, and has been estimated to synthesize up to 50% of the dinitrogen gas emitted into our atmosphere from the oceans. Strikingly, the anammox process relies on the highly unusual, extremely reactive intermediate hydrazine, a compound also used as a rocket fuel because of its high reducing power. So far, the enzymatic mechanism by which hydrazine is synthesized is unknown. Here we report the 2.7 A resolution crystal structure, as well as biophysical and spectroscopic studies, of a hydrazine synthase multiprotein complex isolated from the anammox organism Kuenenia stuttgartiensis. The structure shows an elongated dimer of heterotrimers, each of which has two unique c-type haem-containing active sites, as well as an interaction point for a redox partner. Furthermore, a system of tunnels connects these active sites. The crystal structure implies a two-step mechanism for hydrazine synthesis: a three-electron reduction of nitric oxide to hydroxylamine at the active site of the gamma-subunit and its subsequent condensation with ammonia, yielding hydrazine in the active centre of the alpha-subunit. Our results provide the first, to our knowledge, detailed structural insight into the mechanism of biological hydrazine synthesis, which is of major significance for our understanding of the conversion of nitrogenous compounds in nature.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dietl, Andreas -- Ferousi, Christina -- Maalcke, Wouter J -- Menzel, Andreas -- de Vries, Simon -- Keltjens, Jan T -- Jetten, Mike S M -- Kartal, Boran -- Barends, Thomas R M -- P41-GM103311/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Nov 19;527(7578):394-7. doi: 10.1038/nature15517. Epub 2015 Oct 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany. ; Department of Microbiology, Institute for Water and Wetland Research, Radboud University Nijmegen, 6525 AJ Nijmegen, The Netherlands. ; Swiss Light Source, Paul Scherrer Institute, 5232 Villigen, Switzerland. ; Department of Biotechnology, Delft University of Technology, Delft, The Netherlands. ; Department of Biochemistry and Microbiology, Laboratory of Microbiology, Gent University, Gent, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26479033" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteria/*enzymology ; Catalytic Domain ; Crystallography, X-Ray ; Hydrazines/*metabolism ; Hydroxylamine/metabolism ; Metalloproteins/chemistry/metabolism ; Models, Molecular ; Multienzyme Complexes/*chemistry/*metabolism ; Nitric Oxide/metabolism ; Protein Multimerization
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    Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis (2015)
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    Publication Date: 2015-08-19
    Description: Synaptotagmin-1 and neuronal SNARE proteins have central roles in evoked synchronous neurotransmitter release; however, it is unknown how they cooperate to trigger synaptic vesicle fusion. Here we report atomic-resolution crystal structures of Ca(2+)- and Mg(2+)-bound complexes between synaptotagmin-1 and the neuronal SNARE complex, one of which was determined with diffraction data from an X-ray free-electron laser, leading to an atomic-resolution structure with accurate rotamer assignments for many side chains. The structures reveal several interfaces, including a large, specific, Ca(2+)-independent and conserved interface. Tests of this interface by mutagenesis suggest that it is essential for Ca(2+)-triggered neurotransmitter release in mouse hippocampal neuronal synapses and for Ca(2+)-triggered vesicle fusion in a reconstituted system. We propose that this interface forms before Ca(2+) triggering, moves en bloc as Ca(2+) influx promotes the interactions between synaptotagmin-1 and the plasma membrane, and consequently remodels the membrane to promote fusion, possibly in conjunction with other interfaces.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607316/" 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/PMC4607316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Qiangjun -- Lai, Ying -- Bacaj, Taulant -- Zhao, Minglei -- Lyubimov, Artem Y -- Uervirojnangkoorn, Monarin -- Zeldin, Oliver B -- Brewster, Aaron S -- Sauter, Nicholas K -- Cohen, Aina E -- Soltis, S Michael -- Alonso-Mori, Roberto -- Chollet, Matthieu -- Lemke, Henrik T -- Pfuetzner, Richard A -- Choi, Ucheor B -- Weis, William I -- Diao, Jiajie -- Sudhof, Thomas C -- Brunger, Axel T -- GM095887/GM/NIGMS NIH HHS/ -- GM102520/GM/NIGMS NIH HHS/ -- MH086403/MH/NIMH NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- P41GM103393/GM/NIGMS NIH HHS/ -- P50 MH086403/MH/NIMH NIH HHS/ -- R01 GM077071/GM/NIGMS NIH HHS/ -- R01 GM095887/GM/NIGMS NIH HHS/ -- R01 GM102520/GM/NIGMS NIH HHS/ -- R37 MH063105/MH/NIMH NIH HHS/ -- R37MH63105/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 3;525(7567):62-7. doi: 10.1038/nature14975. Epub 2015 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA. ; Departments of Neurology and Neurological Sciences, Photon Science, and Structural Biology, Stanford University, Stanford, California 94305, USA. ; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; SLAC National Accelerator Laboratory, Stanford, California 94305, USA. ; Departments of Structural Biology, Molecular and Cellular Physiology, and Photon Science, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26280336" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites/genetics ; Calcium/chemistry/metabolism ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Electrons ; *Exocytosis ; Hippocampus/cytology ; Lasers ; Magnesium/chemistry/metabolism ; Membrane Fusion ; Mice ; Models, Biological ; Models, Molecular ; Mutation/genetics ; Neurons/chemistry/cytology/*metabolism/secretion ; SNARE Proteins/*chemistry/genetics/*metabolism ; Synaptic Transmission ; Synaptic Vesicles/chemistry/metabolism/secretion ; Synaptotagmins/*chemistry/genetics/*metabolism
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    The rapid rise of a research nation (2015)
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    Publication Date: 2015-12-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Yingying -- England -- Nature. 2015 Dec 17;528(7582):S170-3. doi: 10.1038/528S170a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26673023" target="_blank"〉PubMed〈/a〉
    Keywords: Biological Science Disciplines ; Chemistry ; China ; Diffusion of Innovation ; Ecology ; Economic Recession ; Humans ; International Cooperation ; Nobel Prize ; Physics ; Research/economics/manpower/standards/*statistics & numerical data ; Research Personnel/education/standards/supply & distribution ; Time Factors
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    Structure and mechanism of an active lipid-linked oligosaccharide flippase (2015)
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    Publication Date: 2015-08-13
    Description: The flipping of membrane-embedded lipids containing large, polar head groups is slow and energetically unfavourable, and is therefore catalysed by flippases, the mechanisms of which are unknown. A prominent example of a flipping reaction is the translocation of lipid-linked oligosaccharides that serve as donors in N-linked protein glycosylation. In Campylobacter jejuni, this process is catalysed by the ABC transporter PglK. Here we present a mechanism of PglK-catalysed lipid-linked oligosaccharide flipping based on crystal structures in distinct states, a newly devised in vitro flipping assay, and in vivo studies. PglK can adopt inward- and outward-facing conformations in vitro, but only outward-facing states are required for flipping. While the pyrophosphate-oligosaccharide head group of lipid-linked oligosaccharides enters the translocation cavity and interacts with positively charged side chains, the lipidic polyprenyl tail binds and activates the transporter but remains exposed to the lipid bilayer during the reaction. The proposed mechanism is distinct from the classical alternating-access model applied to other transporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perez, Camilo -- Gerber, Sabina -- Boilevin, Jeremy -- Bucher, Monika -- Darbre, Tamis -- Aebi, Markus -- Reymond, Jean-Louis -- Locher, Kaspar P -- England -- Nature. 2015 Aug 27;524(7566):433-8. doi: 10.1038/nature14953. Epub 2015 Aug 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biology and Biophysics, ETH Zurich, CH-8093 Zurich, Switzerland. ; Department of Chemistry and Biochemistry, University of Berne, CH-3012 Berne, Switzerland. ; Institute of Microbiology, ETH Zurich, CH-8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26266984" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/*chemistry/*metabolism ; Adenosine Triphosphatases/chemistry/metabolism ; Adenosine Triphosphate/metabolism ; *Biocatalysis ; Campylobacter jejuni/cytology/*enzymology/metabolism ; Crystallography, X-Ray ; Hydrolysis ; Lipid Bilayers/metabolism ; Lipopolysaccharides/*metabolism ; Models, Molecular ; Protein Conformation ; Structure-Activity Relationship
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    Structural basis for retroviral integration into nucleosomes (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-06-11
    Description: Retroviral integration is catalysed by a tetramer of integrase (IN) assembled on viral DNA ends in a stable complex, known as the intasome. How the intasome interfaces with chromosomal DNA, which exists in the form of nucleosomal arrays, is currently unknown. Here we show that the prototype foamy virus (PFV) intasome is proficient at stable capture of nucleosomes as targets for integration. Single-particle cryo-electron microscopy reveals a multivalent intasome-nucleosome interface involving both gyres of nucleosomal DNA and one H2A-H2B heterodimer. While the histone octamer remains intact, the DNA is lifted from the surface of the H2A-H2B heterodimer to allow integration at strongly preferred superhelix location +/-3.5 positions. Amino acid substitutions disrupting these contacts impinge on the ability of the intasome to engage nucleosomes in vitro and redistribute viral integration sites on the genomic scale. Our findings elucidate the molecular basis for nucleosome capture by the viral DNA recombination machinery and the underlying nucleosome plasticity that allows integration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530500/" 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/PMC4530500/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maskell, Daniel P -- Renault, Ludovic -- Serrao, Erik -- Lesbats, Paul -- Matadeen, Rishi -- Hare, Stephen -- Lindemann, Dirk -- Engelman, Alan N -- Costa, Alessandro -- Cherepanov, Peter -- P50 GM082251-06/GM/NIGMS NIH HHS/ -- R01 AI070042/AI/NIAID NIH HHS/ -- R01 AI070042-08/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Jul 16;523(7560):366-9. doi: 10.1038/nature14495. Epub 2015 Jun 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Chromatin Structure and Mobile DNA, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK. ; 1] Architecture and Dynamics of Macromolecular Machines, Clare Hall Laboratories, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK [2] National Institute for Biological Standards and Control, Microscopy and Imaging, Blanche Lane, South Mimms EN6 3QG, UK. ; Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA. ; NeCEN, Gorlaeus Laboratory, Einsteinweg 55, Leiden, 2333, the Netherlands. ; Division of Medicine, Imperial College London, St-Mary's Campus, Norfolk Place, London W2 1PG, UK. ; Institute of Virology, Technische Universitat Dresden, Fetscherstr. 74, Dresden 01307, Germany. ; Architecture and Dynamics of Macromolecular Machines, Clare Hall Laboratories, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK. ; 1] Chromatin Structure and Mobile DNA, The Francis Crick Institute, Blanche Lane, South Mimms EN6 3LD, UK [2] Division of Medicine, Imperial College London, St-Mary's Campus, Norfolk Place, London W2 1PG, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26061770" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Substitution ; Binding Sites/genetics ; Cryoelectron Microscopy ; DNA/genetics/metabolism/ultrastructure ; Genome/genetics ; Histones/chemistry/metabolism/ultrastructure ; Integrases/metabolism ; Models, Molecular ; Nucleosomes/*chemistry/genetics/ultrastructure/*virology ; Protein Multimerization ; Recombination, Genetic ; Spumavirus/chemistry/genetics/*metabolism/ultrastructure ; *Virus Integration
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    A four-helix bundle stores copper for methane oxidation (2015)
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    Publication Date: 2015-08-27
    Description: Methane-oxidizing bacteria (methanotrophs) require large quantities of copper for the membrane-bound (particulate) methane monooxygenase. Certain methanotrophs are also able to switch to using the iron-containing soluble methane monooxygenase to catalyse methane oxidation, with this switchover regulated by copper. Methane monooxygenases are nature's primary biological mechanism for suppressing atmospheric levels of methane, a potent greenhouse gas. Furthermore, methanotrophs and methane monooxygenases have enormous potential in bioremediation and for biotransformations producing bulk and fine chemicals, and in bioenergy, particularly considering increased methane availability from renewable sources and hydraulic fracturing of shale rock. Here we discover and characterize a novel copper storage protein (Csp1) from the methanotroph Methylosinus trichosporium OB3b that is exported from the cytosol, and stores copper for particulate methane monooxygenase. Csp1 is a tetramer of four-helix bundles with each monomer binding up to 13 Cu(I) ions in a previously unseen manner via mainly Cys residues that point into the core of the bundle. Csp1 is the first example of a protein that stores a metal within an established protein-folding motif. This work provides a detailed insight into how methanotrophs accumulate copper for the oxidation of methane. Understanding this process is essential if the wide-ranging biotechnological applications of methanotrophs are to be realized. Cytosolic homologues of Csp1 are present in diverse bacteria, thus challenging the dogma that such organisms do not use copper in this location.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561512/" 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/PMC4561512/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vita, Nicolas -- Platsaki, Semeli -- Basle, Arnaud -- Allen, Stephen J -- Paterson, Neil G -- Crombie, Andrew T -- Murrell, J Colin -- Waldron, Kevin J -- Dennison, Christopher -- 098375/Z/12/Z/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Sep 3;525(7567):140-3. doi: 10.1038/nature14854. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cell and Molecular Biosciences, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. ; Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK. ; School of Environmental Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26308900" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Bacterial Proteins/*chemistry/*metabolism ; Copper/*metabolism ; Crystallography, X-Ray ; Cytosol/metabolism ; Methane/chemistry/*metabolism ; Methylosinus trichosporium/*chemistry/enzymology ; Models, Molecular ; Oxidation-Reduction ; Oxygenases/metabolism ; Protein Folding ; Protein Structure, Secondary
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    Rational design of alpha-helical tandem repeat proteins with closed architectures (2015)
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    Publication Date: 2015-12-18
    Description: Tandem repeat proteins, which are formed by repetition of modular units of protein sequence and structure, play important biological roles as macromolecular binding and scaffolding domains, enzymes, and building blocks for the assembly of fibrous materials. The modular nature of repeat proteins enables the rapid construction and diversification of extended binding surfaces by duplication and recombination of simple building blocks. The overall architecture of tandem repeat protein structures--which is dictated by the internal geometry and local packing of the repeat building blocks--is highly diverse, ranging from extended, super-helical folds that bind peptide, DNA, and RNA partners, to closed and compact conformations with internal cavities suitable for small molecule binding and catalysis. Here we report the development and validation of computational methods for de novo design of tandem repeat protein architectures driven purely by geometric criteria defining the inter-repeat geometry, without reference to the sequences and structures of existing repeat protein families. We have applied these methods to design a series of closed alpha-solenoid repeat structures (alpha-toroids) in which the inter-repeat packing geometry is constrained so as to juxtapose the amino (N) and carboxy (C) termini; several of these designed structures have been validated by X-ray crystallography. Unlike previous approaches to tandem repeat protein engineering, our design procedure does not rely on template sequence or structural information taken from natural repeat proteins and hence can produce structures unlike those seen in nature. As an example, we have successfully designed and validated closed alpha-solenoid repeats with a left-handed helical architecture that--to our knowledge--is not yet present in the protein structure database.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727831/" 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/PMC4727831/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Doyle, Lindsey -- Hallinan, Jazmine -- Bolduc, Jill -- Parmeggiani, Fabio -- Baker, David -- Stoddard, Barry L -- Bradley, Philip -- R01 GM049857/GM/NIGMS NIH HHS/ -- R01 GM115545/GM/NIGMS NIH HHS/ -- R01GM49857/GM/NIGMS NIH HHS/ -- R21 GM106117/GM/NIGMS NIH HHS/ -- R21GM106117/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Dec 24;528(7583):585-8. doi: 10.1038/nature16191. Epub 2015 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, Washington 98109, USA. ; Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. ; Institute for Protein Design, University of Washington, Seattle, Washington 98195, USA. ; Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA. ; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, Washington 98019, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26675735" target="_blank"〉PubMed〈/a〉
    Keywords: *Amino Acid Motifs ; *Bioengineering ; *Computer Simulation ; Crystallography, X-Ray ; Databases, Protein ; Models, Molecular ; *Protein Structure, Secondary ; Proteins/*chemistry ; Reproducibility of Results
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    Structural insights into the bacterial carbon-phosphorus lyase machinery (2015)
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    Publication Date: 2015-08-19
    Description: Phosphorus is required for all life and microorganisms can extract it from their environment through several metabolic pathways. When phosphate is in limited supply, some bacteria are able to use phosphonate compounds, which require specialized enzymatic machinery to break the stable carbon-phosphorus (C-P) bond. Despite its importance, the details of how this machinery catabolizes phosphonates remain unknown. Here we determine the crystal structure of the 240-kilodalton Escherichia coli C-P lyase core complex (PhnG-PhnH-PhnI-PhnJ; PhnGHIJ), and show that it is a two-fold symmetric hetero-octamer comprising an intertwined network of subunits with unexpected self-homologies. It contains two potential active sites that probably couple phosphonate compounds to ATP and subsequently hydrolyse the C-P bond. We map the binding site of PhnK on the complex using electron microscopy, and show that it binds to a conserved insertion domain of PhnJ. Our results provide a structural basis for understanding microbial phosphonate breakdown.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617613/" 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/PMC4617613/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seweryn, Paulina -- Van, Lan Bich -- Kjeldgaard, Morten -- Russo, Christopher J -- Passmore, Lori A -- Hove-Jensen, Bjarne -- Jochimsen, Bjarne -- Brodersen, Ditlev E -- MC_U105192715/Medical Research Council/United Kingdom -- England -- Nature. 2015 Sep 3;525(7567):68-72. doi: 10.1038/nature14683. Epub 2015 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10c, DK-8000 Aarhus C, Denmark. ; Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26280334" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Binding Sites ; Biocatalysis ; Carbon/chemistry/metabolism ; Conserved Sequence ; Crystallography, X-Ray ; Escherichia coli/*enzymology ; Escherichia coli Proteins/*chemistry/*metabolism/ultrastructure ; Hydrolysis ; Iron/chemistry/metabolism ; Lyases/*chemistry/*metabolism/ultrastructure ; Microscopy, Electron ; Models, Molecular ; Organophosphonates/metabolism ; Phosphorus/chemistry/metabolism ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Sulfur/chemistry/metabolism
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    In situ structural analysis of the human nuclear pore complex (2015)
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    Publication Date: 2015-09-30
    Description: Nuclear pore complexes are fundamental components of all eukaryotic cells that mediate nucleocytoplasmic exchange. Determining their 110-megadalton structure imposes a formidable challenge and requires in situ structural biology approaches. Of approximately 30 nucleoporins (Nups), 15 are structured and form the Y and inner-ring complexes. These two major scaffolding modules assemble in multiple copies into an eight-fold rotationally symmetric structure that fuses the inner and outer nuclear membranes to form a central channel of ~60 nm in diameter. The scaffold is decorated with transport-channel Nups that often contain phenylalanine-repeat sequences and mediate the interaction with cargo complexes. Although the architectural arrangement of parts of the Y complex has been elucidated, it is unclear how exactly it oligomerizes in situ. Here we combine cryo-electron tomography with mass spectrometry, biochemical analysis, perturbation experiments and structural modelling to generate, to our knowledge, the most comprehensive architectural model of the human nuclear pore complex to date. Our data suggest previously unknown protein interfaces across Y complexes and to inner-ring complex members. We show that the transport-channel Nup358 (also known as Ranbp2) has a previously unanticipated role in Y-complex oligomerization. Our findings blur the established boundaries between scaffold and transport-channel Nups. We conclude that, similar to coated vesicles, several copies of the same structural building block--although compositionally identical--engage in different local sets of interactions and conformations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉von Appen, Alexander -- Kosinski, Jan -- Sparks, Lenore -- Ori, Alessandro -- DiGuilio, Amanda L -- Vollmer, Benjamin -- Mackmull, Marie-Therese -- Banterle, Niccolo -- Parca, Luca -- Kastritis, Panagiotis -- Buczak, Katarzyna -- Mosalaganti, Shyamal -- Hagen, Wim -- Andres-Pons, Amparo -- Lemke, Edward A -- Bork, Peer -- Antonin, Wolfram -- Glavy, Joseph S -- Bui, Khanh Huy -- Beck, Martin -- 1R21AG047433-01/AG/NIA NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):140-3. doi: 10.1038/nature15381. Epub 2015 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117 Heidelberg, Germany. ; Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, 507 River St., Hoboken, New Jersey 07030, USA. ; Friedrich Miescher Laboratory of the Max Planck Society, Spemannstrasse 39, 72076 Tubingen, Germany. ; Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec H3A 0C7, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26416747" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; *Cryoelectron Microscopy ; HeLa Cells ; Humans ; Mass Spectrometry ; Models, Molecular ; Molecular Chaperones/chemistry/metabolism/ultrastructure ; Nuclear Envelope/metabolism ; Nuclear Pore/*chemistry/metabolism/*ultrastructure ; Nuclear Pore Complex Proteins/*chemistry/metabolism/*ultrastructure ; Protein Conformation ; Protein Multimerization ; Protein Stability
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    Structure of the eukaryotic MCM complex at 3.8 A (2015)
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    Publication Date: 2015-07-30
    Description: DNA replication in eukaryotes is strictly regulated by several mechanisms. A central step in this replication is the assembly of the heterohexameric minichromosome maintenance (MCM2-7) helicase complex at replication origins during G1 phase as an inactive double hexamer. Here, using cryo-electron microscopy, we report a near-atomic structure of the MCM2-7 double hexamer purified from yeast G1 chromatin. Our structure shows that two single hexamers, arranged in a tilted and twisted fashion through interdigitated amino-terminal domain interactions, form a kinked central channel. Four constricted rings consisting of conserved interior beta-hairpins from the two single hexamers create a narrow passageway that tightly fits duplex DNA. This narrow passageway, reinforced by the offset of the two single hexamers at the double hexamer interface, is flanked by two pairs of gate-forming subunits, MCM2 and MCM5. These unusual features of the twisted and tilted single hexamers suggest a concerted mechanism for the melting of origin DNA that requires structural deformation of the intervening DNA.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Ningning -- Zhai, Yuanliang -- Zhang, Yixiao -- Li, Wanqiu -- Yang, Maojun -- Lei, Jianlin -- Tye, Bik-Kwoon -- Gao, Ning -- England -- Nature. 2015 Aug 13;524(7564):186-91. doi: 10.1038/nature14685. Epub 2015 Jul 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ministry of Education Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; 1] Division of Life Science, Hong Kong Universityof Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China [2] Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. ; 1] Division of Life Science, Hong Kong Universityof Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China [2] Department of Molecular Biology and Genetics, College of Agriculture and Life Sciences, Cornell University, Ithaca, New York 14853, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26222030" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cell Cycle Proteins/chemistry/metabolism/ultrastructure ; Chromatin/chemistry ; Conserved Sequence ; *Cryoelectron Microscopy ; DNA/chemistry/metabolism/ultrastructure ; DNA-Directed DNA Polymerase/chemistry/ultrastructure ; G1 Phase ; Minichromosome Maintenance Proteins/*chemistry/metabolism/*ultrastructure ; Models, Biological ; Models, Molecular ; Multienzyme Complexes/chemistry/ultrastructure ; Nucleic Acid Denaturation ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Protein Subunits/*chemistry/metabolism ; Replication Origin ; Saccharomyces cerevisiae/*chemistry/*ultrastructure ; Saccharomyces cerevisiae Proteins/chemistry/metabolism/ultrastructure
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    [This Week in Science] Synthetic twists among lipids (2016)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2016-04-29
    Description: Author: Jake Yeston
    Keywords: Chemistry
    Print ISSN: 0036-8075
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    [This Week in Science] Temporarily caught in a bind (2016)
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    Publication Date: 2016-03-18
    Description: Author: Marc S. Lavine
    Keywords: Chemistry
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    [Perspective] Quantum dynamics in the smallest water droplet (2016)
    American Association for the Advancement of Science (AAAS)
    In: Science
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    Publication Date: 2016-03-18
    Description: Water plays a central role in scientific disciplines ranging from geology to astronomy to biology. Yet it is an extraordinarily dif cult liquid to understand because of its complex, ever-changing patterns of hydrogen bonds. Studies of small water clusters have provided important insights into the concerted hydrogen-bond motions that can occur in water. These studies are also crucial for developing an accurate potential function for simulating the properties of liquid water and ice (1). On page 1310 of this issue, Richardson et al. (2) provide evidence for a concerted type of motion in which two hydrogen bonds in a water cluster are broken simultaneously (see the figure). The results have implications for many areas of scientific study, including the chemistry of polar solvents, the conformations of proteins, and the dissolution of ions in minerals. Author: David C. Clary
    Keywords: Chemistry
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    [Editors' Choice] Beyond blank slates in the lab notebook (2016)
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    In: Science
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    Publication Date: 2016-03-18
    Description: Author: Jake Yeston
    Keywords: Chemistry
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    [Perspective] Surprised by selectivity (2016)
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    In: Science
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    Publication Date: 2016-03-04
    Description: Lower olefins, particularly ethylene (C2H4), propylene (C3H6), and butylene (C4H8), are important intermediates in the manufacture of products such as plastics, solvents, paints, and medicines. They are produced worldwide in amounts exceeding 200 million tons per year (see the photo) (1), mostly from crude oil. More recent approaches use methanol or synthesis gas (syngas; a mixture of carbon monoxide and hydrogen) as feedstocks, but capital investments are high and/or selectivities to lower olefins limited. A bifunctional catalyst reported by Jiao et al. on page 1065 of this issue (2) enables the direct conversion of synthesis gas to lower olefins with a surprisingly high selectivity. Author: Krijn P. de Jong
    Keywords: Chemistry
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    An atomic structure of human gamma-secretase (2015)
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    Publication Date: 2015-08-19
    Description: Dysfunction of the intramembrane protease gamma-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human gamma-secretase at 3.4 A resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of gamma-secretase function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568306/" 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/PMC4568306/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bai, Xiao-chen -- Yan, Chuangye -- Yang, Guanghui -- Lu, Peilong -- Ma, Dan -- Sun, Linfeng -- Zhou, Rui -- Scheres, Sjors H W -- Shi, Yigong -- MC_UP_A025_101/Medical Research Council/United Kingdom -- MC_UP_A025_1013/Medical Research Council/United Kingdom -- England -- Nature. 2015 Sep 10;525(7568):212-7. doi: 10.1038/nature14892. Epub 2015 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26280335" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/genetics ; Amyloid Precursor Protein ; Secretases/*chemistry/genetics/metabolism/*ultrastructure ; Binding Sites ; *Cryoelectron Microscopy ; Humans ; Membrane Glycoproteins/*chemistry/metabolism/*ultrastructure ; Models, Molecular ; Mutation ; Presenilin-1/*chemistry/genetics/*ultrastructure ; Protein Structure, Tertiary ; Protein Subunits/chemistry/genetics/metabolism
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    Propagation of conformational changes during mu-opioid receptor activation (2015)
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    Publication Date: 2015-08-08
    Description: micro-Opioid receptors (microORs) are G-protein-coupled receptors that are activated by a structurally diverse spectrum of natural and synthetic agonists including endogenous endorphin peptides, morphine and methadone. The recent structures of the muOR in inactive and agonist-induced active states (Huang et al., ref. 2) provide snapshots of the receptor at the beginning and end of a signalling event, but little is known about the dynamic sequence of events that span these two states. Here we use solution-state NMR to examine the process of muOR activation using a purified receptor (mouse sequence) preparation in an amphiphile membrane-like environment. We obtain spectra of the muOR in the absence of ligand, and in the presence of the high-affinity agonist BU72 alone, or with BU72 and a G protein mimetic nanobody. Our results show that conformational changes in transmembrane segments 5 and 6 (TM5 and TM6), which are required for the full engagement of a G protein, are almost completely dependent on the presence of both the agonist and the G protein mimetic nanobody, revealing a weak allosteric coupling between the agonist-binding pocket and the G-protein-coupling interface (TM5 and TM6), similar to that observed for the beta2-adrenergic receptor. Unexpectedly, in the presence of agonist alone, we find larger spectral changes involving intracellular loop 1 and helix 8 compared to changes in TM5 and TM6. These results suggest that one or both of these domains may play a role in the initial interaction with the G protein, and that TM5 and TM6 are only engaged later in the process of complex formation. The initial interactions between the G protein and intracellular loop 1 and/or helix 8 may be involved in G-protein coupling specificity, as has been suggested for other family A G-protein-coupled receptors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sounier, Remy -- Mas, Camille -- Steyaert, Jan -- Laeremans, Toon -- Manglik, Aashish -- Huang, Weijiao -- Kobilka, Brian K -- Demene, Helene -- Granier, Sebastien -- DA036246/DA/NIDA NIH HHS/ -- R37 DA036246/DA/NIDA NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):375-8. doi: 10.1038/nature14680. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Genomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, F-34000 Montpellier, France. ; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. ; Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Centre de Biochimie Structurale, CNRS UMR 5048-INSERM 1054- University of Montpellier, 29 rue de Navacelles, 34090 Montpellier Cedex, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245377" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Animals ; Binding Sites ; Heterotrimeric GTP-Binding Proteins/metabolism ; Lysine/metabolism ; Mice ; Models, Molecular ; Morphinans/chemistry/metabolism/pharmacology ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Protein Conformation/drug effects ; Pyrroles/chemistry/metabolism/pharmacology ; Receptors, Adrenergic, beta-2/chemistry ; Receptors, Opioid, mu/*chemistry/*metabolism ; Single-Chain Antibodies/chemistry/metabolism/pharmacology ; Structure-Activity Relationship ; Substrate Specificity
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    X-ray structure of a mammalian stearoyl-CoA desaturase (2015)
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    Publication Date: 2015-06-23
    Description: Stearoyl-CoA desaturase (SCD) is conserved in all eukaryotes and introduces the first double bond into saturated fatty acyl-CoAs. Because the monounsaturated products of SCD are key precursors of membrane phospholipids, cholesterol esters and triglycerides, SCD is pivotal in fatty acid metabolism. Humans have two SCD homologues (SCD1 and SCD5), while mice have four (SCD1-SCD4). SCD1-deficient mice do not become obese or diabetic when fed a high-fat diet because of improved lipid metabolic profiles and insulin sensitivity. Thus, SCD1 is a pharmacological target in the treatment of obesity, diabetes and other metabolic diseases. SCD1 is an integral membrane protein located in the endoplasmic reticulum, and catalyses the formation of a cis-double bond between the ninth and tenth carbons of stearoyl- or palmitoyl-CoA. The reaction requires molecular oxygen, which is activated by a di-iron centre, and cytochrome b5, which regenerates the di-iron centre. To understand better the structural basis of these characteristics of SCD function, here we crystallize and solve the structure of mouse SCD1 bound to stearoyl-CoA at 2.6 A resolution. The structure shows a novel fold comprising four transmembrane helices capped by a cytosolic domain, and a plausible pathway for lateral substrate access and product egress. The acyl chain of the bound stearoyl-CoA is enclosed in a tunnel buried in the cytosolic domain, and the geometry of the tunnel and the conformation of the bound acyl chain provide a structural basis for the regioselectivity and stereospecificity of the desaturation reaction. The dimetal centre is coordinated by a unique spacial arrangement of nine conserved histidine residues that implies a potentially novel mechanism for oxygen activation. The structure also illustrates a possible route for electron transfer from cytochrome b5 to the di-iron centre.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689147/" 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/PMC4689147/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bai, Yonghong -- McCoy, Jason G -- Levin, Elena J -- Sobrado, Pablo -- Rajashankar, Kanagalaghatta R -- Fox, Brian G -- Zhou, Ming -- P41 GM103403/GM/NIGMS NIH HHS/ -- P41GM103403/GM/NIGMS NIH HHS/ -- R01 DK088057/DK/NIDDK NIH HHS/ -- R01 GM098878/GM/NIGMS NIH HHS/ -- R01 HL086392/HL/NHLBI NIH HHS/ -- R01DK088057/DK/NIDDK NIH HHS/ -- R01GM050853/GM/NIGMS NIH HHS/ -- R01GM098878/GM/NIGMS NIH HHS/ -- R01HL086392/HL/NHLBI NIH HHS/ -- U54 GM094584/GM/NIGMS NIH HHS/ -- U54GM094584/GM/NIGMS NIH HHS/ -- U54GM095315/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 13;524(7564):252-6. doi: 10.1038/nature14549. Epub 2015 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. ; NE-CAT and Department of Chemistry and Chemical Biology, Cornell University, Argonne National Laboratory, Argonne, Illinois 60439, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26098370" target="_blank"〉PubMed〈/a〉
    Keywords: Acyl Coenzyme A/chemistry/metabolism ; Animals ; Binding Sites ; Crystallography, X-Ray ; Cytochromes b5/chemistry/metabolism ; Electron Transport ; Histidine/chemistry/metabolism ; Iron/metabolism ; Mice ; Models, Molecular ; Oxygen/metabolism ; Protein Structure, Tertiary ; Static Electricity ; Stearoyl-CoA Desaturase/*chemistry/metabolism ; Structure-Activity Relationship
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    Cryo-electron microscopy structure of the Slo2.2 Na(+)-activated K(+) channel (2015)
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    Publication Date: 2015-10-06
    Description: Na(+)-activated K(+) channels are members of the Slo family of large conductance K(+) channels that are widely expressed in the brain, where their opening regulates neuronal excitability. These channels fulfil a number of biological roles and have intriguing biophysical properties, including conductance levels that are ten times those of most other K(+) channels and gating sensitivity to intracellular Na(+). Here we present the structure of a complete Na(+)-activated K(+) channel, chicken Slo2.2, in the Na(+)-free state, determined by cryo-electron microscopy at a nominal resolution of 4.5 angstroms. The channel is composed of a large cytoplasmic gating ring, in which resides the Na(+)-binding site and a transmembrane domain that closely resembles voltage-gated K(+) channels. In the structure, the cytoplasmic domain adopts a closed conformation and the ion conduction pore is also closed. The structure reveals features that can explain the unusually high conductance of Slo channels and how contraction of the cytoplasmic gating ring closes the pore.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hite, Richard K -- Yuan, Peng -- Li, Zongli -- Hsuing, Yichun -- Walz, Thomas -- MacKinnon, Roderick -- GM43949/GM/NIGMS NIH HHS/ -- R01 GM043949/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 12;527(7577):198-203. doi: 10.1038/nature14958. Epub 2015 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Rockefeller University and Howard Hughes Medical Institute, 1230 York Avenue, New York, New York 10065, USA. ; Department of Cell Biology and Howard Hughes Medical Institute, 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/26436452" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; *Chickens ; *Cryoelectron Microscopy ; Cytoplasm/metabolism ; Electric Conductivity ; Ion Channel Gating ; Ion Transport ; Models, Molecular ; Potassium Channels/chemistry/metabolism/*ultrastructure ; Protein Structure, Tertiary ; Sodium/metabolism ; Structure-Activity Relationship
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    Gating machinery of InsP3R channels revealed by electron cryomicroscopy (2015)
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    Publication Date: 2015-10-13
    Description: Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are ubiquitous ion channels responsible for cytosolic Ca(2+) signalling and essential for a broad array of cellular processes ranging from contraction to secretion, and from proliferation to cell death. Despite decades of research on InsP3Rs, a mechanistic understanding of their structure-function relationship is lacking. Here we present the first, to our knowledge, near-atomic (4.7 A) resolution electron cryomicroscopy structure of the tetrameric mammalian type 1 InsP3R channel in its apo-state. At this resolution, we are able to trace unambiguously approximately 85% of the protein backbone, allowing us to identify the structural elements involved in gating and modulation of this 1.3-megadalton channel. Although the central Ca(2+)-conduction pathway is similar to other ion channels, including the closely related ryanodine receptor, the cytosolic carboxy termini are uniquely arranged in a left-handed alpha-helical bundle, directly interacting with the amino-terminal domains of adjacent subunits. This configuration suggests a molecular mechanism for allosteric regulation of channel gating by intracellular signals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fan, Guizhen -- Baker, Matthew L -- Wang, Zhao -- Baker, Mariah R -- Sinyagovskiy, Pavel A -- Chiu, Wah -- Ludtke, Steven J -- Serysheva, Irina I -- P41 GM103832/GM/NIGMS NIH HHS/ -- P41GM103832/GM/NIGMS NIH HHS/ -- R01 GM072804/GM/NIGMS NIH HHS/ -- R01 GM079429/GM/NIGMS NIH HHS/ -- R01 GM080139/GM/NIGMS NIH HHS/ -- R01GM072804/GM/NIGMS NIH HHS/ -- R01GM079429/GM/NIGMS NIH HHS/ -- R01GM080139/GM/NIGMS NIH HHS/ -- R21 AR063255/AR/NIAMS NIH HHS/ -- R21 GM100229/GM/NIGMS NIH HHS/ -- R21AR063255/AR/NIAMS NIH HHS/ -- R21GM100229/GM/NIGMS NIH HHS/ -- S10 OD016279/OD/NIH HHS/ -- S10OD016279/OD/NIH HHS/ -- England -- Nature. 2015 Nov 19;527(7578):336-41. doi: 10.1038/nature15249. Epub 2015 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Structural Biology Imaging Center, The University of Texas Medical School at Houston, 6431 Fannin Street, Houston, Texas 77030, USA. ; National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26458101" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Animals ; Apoproteins/chemistry/metabolism/ultrastructure ; Calcium/metabolism ; Calcium Signaling ; *Cryoelectron Microscopy ; Cytosol/chemistry/metabolism ; Inositol 1,4,5-Trisphosphate Receptors/chemistry/*metabolism/*ultrastructure ; Ion Channel Gating ; Models, Molecular ; Protein Folding ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Rats ; Ryanodine Receptor Calcium Release Channel/chemistry/metabolism
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    UbiX is a flavin prenyltransferase required for bacterial ubiquinone biosynthesis (2015)
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    Publication Date: 2015-06-18
    Description: Ubiquinone (also known as coenzyme Q) is a ubiquitous lipid-soluble redox cofactor that is an essential component of electron transfer chains. Eleven genes have been implicated in bacterial ubiquinone biosynthesis, including ubiX and ubiD, which are responsible for decarboxylation of the 3-octaprenyl-4-hydroxybenzoate precursor. Despite structural and biochemical characterization of UbiX as a flavin mononucleotide (FMN)-binding protein, no decarboxylase activity has been detected. Here we report that UbiX produces a novel flavin-derived cofactor required for the decarboxylase activity of UbiD. UbiX acts as a flavin prenyltransferase, linking a dimethylallyl moiety to the flavin N5 and C6 atoms. This adds a fourth non-aromatic ring to the flavin isoalloxazine group. In contrast to other prenyltransferases, UbiX is metal-independent and requires dimethylallyl-monophosphate as substrate. Kinetic crystallography reveals that the prenyltransferase mechanism of UbiX resembles that of the terpene synthases. The active site environment is dominated by pi systems, which assist phosphate-C1' bond breakage following FMN reduction, leading to formation of the N5-C1' bond. UbiX then acts as a chaperone for adduct reorientation, via transient carbocation species, leading ultimately to formation of the dimethylallyl C3'-C6 bond. Our findings establish the mechanism for formation of a new flavin-derived cofactor, extending both flavin and terpenoid biochemical repertoires.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉White, Mark D -- Payne, Karl A P -- Fisher, Karl -- Marshall, Stephen A -- Parker, David -- Rattray, Nicholas J W -- Trivedi, Drupad K -- Goodacre, Royston -- Rigby, Stephen E J -- Scrutton, Nigel S -- Hay, Sam -- Leys, David -- BB/K017802/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/M017702/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2015 Jun 25;522(7557):502-6. doi: 10.1038/nature14559. Epub 2015 Jun 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Synthetic Biology of Fine and Speciality Chemicals, Manchester Institute of Biotechnology, The University of Manchester, Manchester M1 7DN, UK. ; Innovation/Biodomain, Shell International Exploration and Production, Westhollow Technology Center, 3333 Highway 6 South, Houston, Texas 77082-3101, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26083743" target="_blank"〉PubMed〈/a〉
    Keywords: Alkyl and Aryl Transferases/chemistry/metabolism ; Aspergillus niger/enzymology/genetics ; *Biocatalysis ; Carboxy-Lyases/chemistry/genetics/*metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Cycloaddition Reaction ; Decarboxylation ; Dimethylallyltranstransferase/chemistry/genetics/*metabolism ; Electron Transport ; Flavin Mononucleotide/metabolism ; Flavins/biosynthesis/chemistry/*metabolism ; Models, Molecular ; Pseudomonas aeruginosa/*enzymology/genetics/*metabolism ; Ubiquinone/*biosynthesis
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    Crystal structures of a double-barrelled fluoride ion channel (2015)
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    Publication Date: 2015-09-08
    Description: To contend with hazards posed by environmental fluoride, microorganisms export this anion through F(-)-specific ion channels of the Fluc family. Since the recent discovery of Fluc channels, numerous idiosyncratic features of these proteins have been unearthed, including strong selectivity for F(-) over Cl(-) and dual-topology dimeric assembly. To understand the chemical basis for F(-) permeation and how the antiparallel subunits convene to form a F(-)-selective pore, here we solve the crystal structures of two bacterial Fluc homologues in complex with three different monobody inhibitors, with and without F(-) present, to a maximum resolution of 2.1 A. The structures reveal a surprising 'double-barrelled' channel architecture in which two F(-) ion pathways span the membrane, and the dual-topology arrangement includes a centrally coordinated cation, most likely Na(+). F(-) selectivity is proposed to arise from the very narrow pores and an unusual anion coordination that exploits the quadrupolar edges of conserved phenylalanine rings.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stockbridge, Randy B -- Kolmakova-Partensky, Ludmila -- Shane, Tania -- Koide, Akiko -- Koide, Shohei -- Miller, Christopher -- Newstead, Simon -- 102890/Z/13/Z/Wellcome Trust/United Kingdom -- K99 GM111767/GM/NIGMS NIH HHS/ -- K99-GM-111767/GM/NIGMS NIH HHS/ -- R01 GM107023/GM/NIGMS NIH HHS/ -- R01-GM107023/GM/NIGMS NIH HHS/ -- U54 GM087519/GM/NIGMS NIH HHS/ -- U54-GM087519/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Sep 24;525(7570):548-51. doi: 10.1038/nature14981. Epub 2015 Sep 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, Massachusetts 02454, USA. ; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA. ; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QU, UK. ; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26344196" target="_blank"〉PubMed〈/a〉
    Keywords: Anions/chemistry/metabolism/pharmacology ; Bacterial Proteins/*chemistry/*metabolism ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Fluorides/chemistry/*metabolism/*pharmacology ; Ion Channels/*chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Phenylalanine/metabolism ; Protein Conformation
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    Structural insight into substrate preference for TET-mediated oxidation (2015)
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    Publication Date: 2015-11-03
    Description: DNA methylation is an important epigenetic modification. Ten-eleven translocation (TET) proteins are involved in DNA demethylation through iteratively oxidizing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Here we show that human TET1 and TET2 are more active on 5mC-DNA than 5hmC/5fC-DNA substrates. We determine the crystal structures of TET2-5hmC-DNA and TET2-5fC-DNA complexes at 1.80 A and 1.97 A resolution, respectively. The cytosine portion of 5hmC/5fC is specifically recognized by TET2 in a manner similar to that of 5mC in the TET2-5mC-DNA structure, and the pyrimidine base of 5mC/5hmC/5fC adopts an almost identical conformation within the catalytic cavity. However, the hydroxyl group of 5hmC and carbonyl group of 5fC face towards the opposite direction because the hydroxymethyl group of 5hmC and formyl group of 5fC adopt restrained conformations through forming hydrogen bonds with the 1-carboxylate of NOG and N4 exocyclic nitrogen of cytosine, respectively. Biochemical analyses indicate that the substrate preference of TET2 results from the different efficiencies of hydrogen abstraction in TET2-mediated oxidation. The restrained conformation of 5hmC and 5fC within the catalytic cavity may prevent their abstractable hydrogen(s) adopting a favourable orientation for hydrogen abstraction and thus result in low catalytic efficiency. Our studies demonstrate that the substrate preference of TET2 results from the intrinsic value of its substrates at their 5mC derivative groups and suggest that 5hmC is relatively stable and less prone to further oxidation by TET proteins. Therefore, TET proteins are evolutionarily tuned to be less reactive towards 5hmC and facilitate the generation of 5hmC as a potentially stable mark for regulatory functions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hu, Lulu -- Lu, Junyan -- Cheng, Jingdong -- Rao, Qinhui -- Li, Ze -- Hou, Haifeng -- Lou, Zhiyong -- Zhang, Lei -- Li, Wei -- Gong, Wei -- Liu, Mengjie -- Sun, Chang -- Yin, Xiaotong -- Li, Jie -- Tan, Xiangshi -- Wang, Pengcheng -- Wang, Yinsheng -- Fang, Dong -- Cui, Qiang -- Yang, Pengyuan -- He, Chuan -- Jiang, Hualiang -- Luo, Cheng -- Xu, Yanhui -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 5;527(7576):118-22. doi: 10.1038/nature15713. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. ; Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. ; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China. ; Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. ; Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China. ; Laboratory of Structural Biology, Tsinghua University, Beijing 100084, China. ; MOE Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing 100084, China. ; Department of Chemistry, University of California-Riverside, Riverside, California 92521-0403, USA. ; Theoretical Chemistry Institute, Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, USA. ; Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA. ; Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524525" target="_blank"〉PubMed〈/a〉
    Keywords: 5-Methylcytosine/metabolism ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Cytosine/analogs & derivatives/metabolism ; DNA/*chemistry/*metabolism ; DNA Methylation ; DNA-Binding Proteins/*chemistry/*metabolism ; Humans ; Hydrogen Bonding ; Models, Molecular ; Oxidation-Reduction ; Protein Binding ; Proto-Oncogene Proteins/*chemistry/*metabolism ; Substrate Specificity
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65 (2015)
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    Publication Date: 2015-11-10
    Description: At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Xi-Ping -- Karpiak, Joel -- Kroeze, Wesley K -- Zhu, Hu -- Chen, Xin -- Moy, Sheryl S -- Saddoris, Kara A -- Nikolova, Viktoriya D -- Farrell, Martilias S -- Wang, Sheng -- Mangano, Thomas J -- Deshpande, Deepak A -- Jiang, Alice -- Penn, Raymond B -- Jin, Jian -- Koller, Beverly H -- Kenakin, Terry -- Shoichet, Brian K -- Roth, Bryan L -- GM59957/GM/NIGMS NIH HHS/ -- GM71896/GM/NIGMS NIH HHS/ -- P01 HL114471/HL/NHLBI NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- U01 MH104974/MH/NIMH NIH HHS/ -- U19MH082441/MH/NIMH NIH HHS/ -- U54 HD079124/HD/NICHD NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):477-83. doi: 10.1038/nature15699. Epub 2015 Nov 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-7365, USA. ; National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7365, USA. ; Department of Pharmaceutical Chemistry, University of California at San Francisco, Byers Hall, 1700 4th Street, San Francisco, California 94158-2550, USA. ; Center for Integrative Chemical Biology and Drug Discovery (CICBDD), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7363, USA. ; Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA. ; Department of Psychiatry and Carolina Institute for Developmental Disabilities (CIDD), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7146, USA. ; Center for Translational Medicine and Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. ; Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7264, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26550826" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Allosteric Site ; Animals ; Anti-Anxiety Agents/analysis/chemistry/metabolism/pharmacology ; Benzyl Alcohols/analysis/*chemistry/metabolism/*pharmacology ; Conditioning, Classical ; *Drug Discovery ; Fear ; Female ; HEK293 Cells ; Humans ; Ligands ; Lorazepam/analysis/*chemistry/metabolism/*pharmacology ; Male ; Memory/drug effects ; Mice ; Mice, Knockout ; Models, Molecular ; Receptors, G-Protein-Coupled/agonists/antagonists & ; inhibitors/chemistry/deficiency/*metabolism ; Signal Transduction/drug effects ; Triazines/analysis/*chemistry/metabolism/*pharmacology
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    Crystal structure of the RNA-dependent RNA polymerase from influenza C virus (2015)
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    Publication Date: 2015-10-28
    Description: Negative-sense RNA viruses, such as influenza, encode large, multidomain RNA-dependent RNA polymerases that can both transcribe and replicate the viral RNA genome. In influenza virus, the polymerase (FluPol) is composed of three polypeptides: PB1, PB2 and PA/P3. PB1 houses the polymerase active site, whereas PB2 and PA/P3 contain, respectively, cap-binding and endonuclease domains required for transcription initiation by cap-snatching. Replication occurs through de novo initiation and involves a complementary RNA intermediate. Currently available structures of the influenza A and B virus polymerases include promoter RNA (the 5' and 3' termini of viral genome segments), showing FluPol in transcription pre-initiation states. Here we report the structure of apo-FluPol from an influenza C virus, solved by X-ray crystallography to 3.9 A, revealing a new 'closed' conformation. The apo-FluPol forms a compact particle with PB1 at its centre, capped on one face by PB2 and clamped between the two globular domains of P3. Notably, this structure is radically different from those of promoter-bound FluPols. The endonuclease domain of P3 and the domains within the carboxy-terminal two-thirds of PB2 are completely rearranged. The cap-binding site is occluded by PB2, resulting in a conformation that is incompatible with transcription initiation. Thus, our structure captures FluPol in a closed, transcription pre-activation state. This reveals the conformation of newly made apo-FluPol in an infected cell, but may also apply to FluPol in the context of a non-transcribing ribonucleoprotein complex. Comparison of the apo-FluPol structure with those of promoter-bound FluPols allows us to propose a mechanism for FluPol activation. Our study demonstrates the remarkable flexibility of influenza virus RNA polymerase, and aids our understanding of the mechanisms controlling transcription and genome replication.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hengrung, Narin -- El Omari, Kamel -- Serna Martin, Itziar -- Vreede, Frank T -- Cusack, Stephen -- Rambo, Robert P -- Vonrhein, Clemens -- Bricogne, Gerard -- Stuart, David I -- Grimes, Jonathan M -- Fodor, Ervin -- 075491/Z/04/Wellcome Trust/United Kingdom -- 092931/Z/10/Z/Wellcome Trust/United Kingdom -- G1000099/Medical Research Council/United Kingdom -- G1100138/Medical Research Council/United Kingdom -- MR/K000241/1/Medical Research Council/United Kingdom -- England -- Nature. 2015 Nov 5;527(7576):114-7. doi: 10.1038/nature15525. Epub 2015 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. ; Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Oxford OX3 7BN, UK. ; European Molecular Biology Laboratory, Grenoble Outstation and University Grenoble Alpes-Centre National de la Recherche Scientifique-EMBL Unit of Virus Host-Cell Interactions, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France. ; Diamond Light Source Ltd, Harwell Science &Innovation Campus, Didcot OX11 0DE, UK. ; Global Phasing Ltd, Sheraton House, Castle Park, Cambridge CB3 0AX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503046" target="_blank"〉PubMed〈/a〉
    Keywords: Apoenzymes/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Endonucleases/chemistry/metabolism ; Enzyme Activation ; Influenzavirus C/*enzymology ; Models, Molecular ; Peptide Chain Initiation, Translational ; Promoter Regions, Genetic/genetics ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; RNA Caps/metabolism ; RNA Replicase/*chemistry/metabolism ; RNA, Viral/biosynthesis/metabolism ; Ribonucleoproteins/chemistry
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    Structural imprints in vivo decode RNA regulatory mechanisms (2015)
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    Publication Date: 2015-03-25
    Description: Visualizing the physical basis for molecular behaviour inside living cells is a great challenge for biology. RNAs are central to biological regulation, and the ability of RNA to adopt specific structures intimately controls every step of the gene expression program. However, our understanding of physiological RNA structures is limited; current in vivo RNA structure profiles include only two of the four nucleotides that make up RNA. Here we present a novel biochemical approach, in vivo click selective 2'-hydroxyl acylation and profiling experiment (icSHAPE), which enables the first global view, to our knowledge, of RNA secondary structures in living cells for all four bases. icSHAPE of the mouse embryonic stem cell transcriptome versus purified RNA folded in vitro shows that the structural dynamics of RNA in the cellular environment distinguish different classes of RNAs and regulatory elements. Structural signatures at translational start sites and ribosome pause sites are conserved from in vitro conditions, suggesting that these RNA elements are programmed by sequence. In contrast, focal structural rearrangements in vivo reveal precise interfaces of RNA with RNA-binding proteins or RNA-modification sites that are consistent with atomic-resolution structural data. Such dynamic structural footprints enable accurate prediction of RNA-protein interactions and N(6)-methyladenosine (m(6)A) modification genome wide. These results open the door for structural genomics of RNA in living cells and reveal key physiological structures controlling gene expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376618/" 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/PMC4376618/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Spitale, Robert C -- Flynn, Ryan A -- Zhang, Qiangfeng Cliff -- Crisalli, Pete -- Lee, Byron -- Jung, Jong-Wha -- Kuchelmeister, Hannes Y -- Batista, Pedro J -- Torre, Eduardo A -- Kool, Eric T -- Chang, Howard Y -- F30 CA189514/CA/NCI NIH HHS/ -- F30CA189514/CA/NCI NIH HHS/ -- P50 HG007735/HG/NHGRI NIH HHS/ -- P50HG007735/HG/NHGRI NIH HHS/ -- R01 HG004361/HG/NHGRI NIH HHS/ -- R01HG004361/HG/NHGRI NIH HHS/ -- T32 CA009302/CA/NCI NIH HHS/ -- T32AR007422/AR/NIAMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Mar 26;519(7544):486-90. doi: 10.1038/nature14263. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Department of Chemistry, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799993" target="_blank"〉PubMed〈/a〉
    Keywords: Acylation ; Adenosine/analogs & derivatives ; Animals ; Binding Sites ; Cell Survival ; Click Chemistry ; Computational Biology ; Embryonic Stem Cells/cytology/metabolism ; *Gene Expression Regulation/genetics ; Genome/genetics ; Mice ; Models, Molecular ; *Nucleic Acid Conformation ; Protein Biosynthesis/genetics ; RNA/*chemistry/classification/*genetics/metabolism ; RNA-Binding Proteins/metabolism ; Regulatory Sequences, Ribonucleic Acid/genetics ; Ribosomes/metabolism ; Transcriptome/genetics
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    Crystal structure of the dynamin tetramer (2015)
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    Publication Date: 2015-08-25
    Description: The mechanochemical protein dynamin is the prototype of the dynamin superfamily of large GTPases, which shape and remodel membranes in diverse cellular processes. Dynamin forms predominantly tetramers in the cytosol, which oligomerize at the neck of clathrin-coated vesicles to mediate constriction and subsequent scission of the membrane. Previous studies have described the architecture of dynamin dimers, but the molecular determinants for dynamin assembly and its regulation have remained unclear. Here we present the crystal structure of the human dynamin tetramer in the nucleotide-free state. Combining structural data with mutational studies, oligomerization measurements and Markov state models of molecular dynamics simulations, we suggest a mechanism by which oligomerization of dynamin is linked to the release of intramolecular autoinhibitory interactions. We elucidate how mutations that interfere with tetramer formation and autoinhibition can lead to the congenital muscle disorders Charcot-Marie-Tooth neuropathy and centronuclear myopathy, respectively. Notably, the bent shape of the tetramer explains how dynamin assembles into a right-handed helical oligomer of defined diameter, which has direct implications for its function in membrane constriction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reubold, Thomas F -- Faelber, Katja -- Plattner, Nuria -- Posor, York -- Ketel, Katharina -- Curth, Ute -- Schlegel, Jeanette -- Anand, Roopsee -- Manstein, Dietmar J -- Noe, Frank -- Haucke, Volker -- Daumke, Oliver -- Eschenburg, Susanne -- England -- Nature. 2015 Sep 17;525(7569):404-8. doi: 10.1038/nature14880. Epub 2015 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut fur Biophysikalische Chemie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. ; Max-Delbruck-Centrum fur Molekulare Medizin, Kristallographie, Robert-Rossle-Strasse 10, 13125 Berlin, Germany. ; Institut fur Mathematik, Freie Universitat Berlin, Arnimallee 6, 14195 Berlin, Germany. ; Leibniz-Institut fur Molekulare Pharmakologie, Robert-Rossle-Strasse 10, 13125 Berlin, Germany. ; Forschungseinrichtung Strukturanalyse, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. ; Institut fur Chemie und Biochemie, Freie Universitat Berlin, Takustrasse 6, 14195 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26302298" target="_blank"〉PubMed〈/a〉
    Keywords: Charcot-Marie-Tooth Disease ; Crystallography, X-Ray ; Dynamins/*antagonists & inhibitors/*chemistry/genetics/metabolism ; Humans ; Markov Chains ; Models, Molecular ; Molecular Dynamics Simulation ; Mutant Proteins/antagonists & inhibitors/chemistry/genetics/metabolism ; Mutation/genetics ; Myopathies, Structural, Congenital ; Nucleotides ; *Protein Multimerization/genetics ; Structure-Activity Relationship
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    Resensitizing daclatasvir-resistant hepatitis C variants by allosteric modulation of NS5A (2015)
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    Publication Date: 2015-11-05
    Description: It is estimated that more than 170 million people are infected with hepatitis C virus (HCV) worldwide. Clinical trials have demonstrated that, for the first time in human history, the potential exists to eradicate a chronic viral disease using combination therapies that contain only direct-acting antiviral agents. HCV non-structural protein 5A (NS5A) is a multifunctional protein required for several stages of the virus replication cycle. NS5A replication complex inhibitors, exemplified by daclatasvir (DCV; also known as BMS-790052 and Daklinza), belong to the most potent class of direct-acting anti-HCV agents described so far, with in vitro activity in the picomolar (pM) to low nanomolar (nM) range. The potency observed in vitro has translated into clinical efficacy, with HCV RNA declining by ~3-4 log10 in infected patients after administration of single oral doses of DCV. Understanding the exceptional potency of DCV was a key objective of this study. Here we show that although DCV and an NS5A inhibitor analogue (Syn-395) are inactive against certain NS5A resistance variants, combinations of the pair enhance DCV potency by 〉1,000-fold, restoring activity to the pM range. This synergistic effect was validated in vivo using an HCV-infected chimaeric mouse model. The cooperative interaction of a pair of compounds suggests that NS5A protein molecules communicate with each other: one inhibitor binds to resistant NS5A, causing a conformational change that is transmitted to adjacent NS5As, resensitizing resistant NS5A so that the second inhibitor can act to restore inhibition. This unprecedented synergistic anti-HCV activity also enhances the resistance barrier of DCV, providing additional options for HCV combination therapy and new insight into the role of NS5A in the HCV replication cycle.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Jin-Hua -- O'Boyle, Donald R 2nd -- Fridell, Robert A -- Langley, David R -- Wang, Chunfu -- Roberts, Susan B -- Nower, Peter -- Johnson, Benjamin M -- Moulin, Frederic -- Nophsker, Michelle J -- Wang, Ying-Kai -- Liu, Mengping -- Rigat, Karen -- Tu, Yong -- Hewawasam, Piyasena -- Kadow, John -- Meanwell, Nicholas A -- Cockett, Mark -- Lemm, Julie A -- Kramer, Melissa -- Belema, Makonen -- Gao, Min -- England -- Nature. 2015 Nov 12;527(7577):245-8. doi: 10.1038/nature15711. Epub 2015 Nov 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. ; Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. ; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. ; Leads Discovery and Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA. ; Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536115" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Animals ; Antiviral Agents/*pharmacology ; Biphenyl Compounds/*pharmacology ; Cell Line ; Drug Resistance, Viral/*drug effects ; Drug Synergism ; Drug Therapy, Combination ; Hepacivirus/*drug effects/*genetics/metabolism ; Hepatitis C/virology ; Hepatocytes/transplantation ; Humans ; Imidazoles/*pharmacology ; Mice ; Models, Molecular ; Protein Conformation/drug effects ; Protein Multimerization/drug effects ; Protein Structure, Quaternary/drug effects ; Reproducibility of Results ; Viral Nonstructural Proteins/chemistry/genetics/*metabolism ; Virus Replication/drug effects
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    Conformational control of DNA target cleavage by CRISPR-Cas9 (2015)
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    Publication Date: 2015-11-03
    Description: Cas9 is an RNA-guided DNA endonuclease that targets foreign DNA for destruction as part of a bacterial adaptive immune system mediated by clustered regularly interspaced short palindromic repeats (CRISPR). Together with single-guide RNAs, Cas9 also functions as a powerful genome engineering tool in plants and animals, and efforts are underway to increase the efficiency and specificity of DNA targeting for potential therapeutic applications. Studies of off-target effects have shown that DNA binding is far more promiscuous than DNA cleavage, yet the molecular cues that govern strand scission have not been elucidated. Here we show that the conformational state of the HNH nuclease domain directly controls DNA cleavage activity. Using intramolecular Forster resonance energy transfer experiments to detect relative orientations of the Cas9 catalytic domains when associated with on- and off-target DNA, we find that DNA cleavage efficiencies scale with the extent to which the HNH domain samples an activated conformation. We furthermore uncover a surprising mode of allosteric communication that ensures concerted firing of both Cas9 nuclease domains. Our results highlight a proofreading mechanism beyond initial protospacer adjacent motif (PAM) recognition and RNA-DNA base-pairing that serves as a final specificity checkpoint before DNA double-strand break formation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sternberg, Samuel H -- LaFrance, Benjamin -- Kaplan, Matias -- Doudna, Jennifer A -- T32GM007232/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 5;527(7576):110-3. doi: 10.1038/nature15544. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of California, Berkeley, California 94720, USA. ; Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. ; Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA. ; Innovative Genomics Initiative, University of California, Berkeley, California 94720, USA. ; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524520" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Bacterial Proteins/chemistry/metabolism ; Base Pairing ; Binding Sites ; CRISPR-Associated Proteins/*chemistry/*metabolism ; *CRISPR-Cas Systems ; Catalytic Domain ; DNA/chemistry/*metabolism ; DNA Breaks, Double-Stranded ; *DNA Cleavage ; Endonucleases/chemistry/*metabolism ; Fluorescence Resonance Energy Transfer ; *Genetic Engineering ; Models, Molecular ; RNA, Guide/chemistry/metabolism ; Streptococcus pyogenes
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    Structural insights into micro-opioid receptor activation (2015)
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    Publication Date: 2015-08-08
    Description: Activation of the mu-opioid receptor (muOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for muOR activation, here we report a 2.1 A X-ray crystal structure of the murine muOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the muOR binding pocket are subtle and differ from those observed for agonist-bound structures of the beta2-adrenergic receptor (beta2AR) and the M2 muscarinic receptor. Comparison with active beta2AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the muOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639397/" 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/PMC4639397/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Weijiao -- Manglik, Aashish -- Venkatakrishnan, A J -- Laeremans, Toon -- Feinberg, Evan N -- Sanborn, Adrian L -- Kato, Hideaki E -- Livingston, Kathryn E -- Thorsen, Thor S -- Kling, Ralf C -- Granier, Sebastien -- Gmeiner, Peter -- Husbands, Stephen M -- Traynor, John R -- Weis, William I -- Steyaert, Jan -- Dror, Ron O -- Kobilka, Brian K -- R01GM083118/GM/NIGMS NIH HHS/ -- R37 DA036246/DA/NIDA NIH HHS/ -- R37DA036246/DA/NIDA NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Aug 20;524(7565):315-21. doi: 10.1038/nature14886. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA. ; Department of Computer Science, Stanford University, 318 Campus Drive, Stanford, California 94305, USA. ; Institute for Computational and Mathematical Engineering, Stanford University, 475 Via Ortega, Stanford, California 94305, USA. ; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium. ; Structural Biology Research Center, VIB, Pleinlaan 2, B-1050 Brussels, Belgium. ; Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Chemistry and Pharmacy, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany. ; Institut de Genomique Fonctionnelle, CNRS UMR-5203 INSERM U1191, University of Montpellier, F-34000 Montpellier, France. ; Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK. ; Department of Structural Biology, Stanford University School of Medicine, 299 Campus Drive, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245379" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Animals ; Binding Sites ; Crystallography, X-Ray ; Heterotrimeric GTP-Binding Proteins/chemistry/metabolism ; Mice ; Models, Molecular ; Molecular Dynamics Simulation ; Morphinans/chemistry/metabolism/pharmacology ; Protein Stability/drug effects ; Protein Structure, Tertiary ; Pyrroles/chemistry/metabolism/pharmacology ; Receptor, Muscarinic M2/chemistry ; Receptors, Adrenergic, beta-2/chemistry ; Receptors, Opioid, mu/agonists/*chemistry/*metabolism ; Single-Chain Antibodies/chemistry/pharmacology ; Structure-Activity Relationship
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    Initiation of translation in bacteria by a structured eukaryotic IRES RNA (2015)
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    Publication Date: 2015-02-06
    Description: The central dogma of gene expression (DNA to RNA to protein) is universal, but in different domains of life there are fundamental mechanistic differences within this pathway. For example, the canonical molecular signals used to initiate protein synthesis in bacteria and eukaryotes are mutually exclusive. However, the core structures and conformational dynamics of ribosomes that are responsible for the translation steps that take place after initiation are ancient and conserved across the domains of life. We wanted to explore whether an undiscovered RNA-based signal might be able to use these conserved features, bypassing mechanisms specific to each domain of life, and initiate protein synthesis in both bacteria and eukaryotes. Although structured internal ribosome entry site (IRES) RNAs can manipulate ribosomes to initiate translation in eukaryotic cells, an analogous RNA structure-based mechanism has not been observed in bacteria. Here we report our discovery that a eukaryotic viral IRES can initiate translation in live bacteria. We solved the crystal structure of this IRES bound to a bacterial ribosome to 3.8 A resolution, revealing that despite differences between bacterial and eukaryotic ribosomes this IRES binds directly to both and occupies the space normally used by transfer RNAs. Initiation in both bacteria and eukaryotes depends on the structure of the IRES RNA, but in bacteria this RNA uses a different mechanism that includes a form of ribosome repositioning after initial recruitment. This IRES RNA bridges billions of years of evolutionary divergence and provides an example of an RNA structure-based translation initiation signal capable of operating in two domains of life.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352134/" 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/PMC4352134/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Colussi, Timothy M -- Costantino, David A -- Zhu, Jianyu -- Donohue, John Paul -- Korostelev, Andrei A -- Jaafar, Zane A -- Plank, Terra-Dawn M -- Noller, Harry F -- Kieft, Jeffrey S -- GM-103105/GM/NIGMS NIH HHS/ -- GM-17129/GM/NIGMS NIH HHS/ -- GM-59140/GM/NIGMS NIH HHS/ -- GM-81346/GM/NIGMS NIH HHS/ -- GM-97333/GM/NIGMS NIH HHS/ -- R01 GM097333/GM/NIGMS NIH HHS/ -- R01 GM106105/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Mar 5;519(7541):110-3. doi: 10.1038/nature14219. Epub 2015 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA [2] Howard Hughes Medical Institute, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA. ; Center for Molecular Biology of RNA and Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California at Santa Cruz, Santa Cruz, California 95064, USA. ; Department of Biochemistry and Molecular Genetics, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652826" target="_blank"〉PubMed〈/a〉
    Keywords: Bacteria/*genetics ; Base Sequence ; Conserved Sequence/genetics ; Crystallography, X-Ray ; Dicistroviridae/genetics ; Eukaryota/*genetics ; Models, Molecular ; *Nucleic Acid Conformation ; Peptide Chain Initiation, Translational/genetics ; Protein Biosynthesis/*genetics ; RNA/*chemistry/*genetics/metabolism ; RNA, Bacterial/chemistry/genetics/metabolism ; RNA, Viral/chemistry/genetics/metabolism ; Ribosomes/chemistry/*metabolism
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    The DNA glycosylase AlkD uses a non-base-flipping mechanism to excise bulky lesions (2015)
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    Publication Date: 2015-11-03
    Description: Threats to genomic integrity arising from DNA damage are mitigated by DNA glycosylases, which initiate the base excision repair pathway by locating and excising aberrant nucleobases. How these enzymes find small modifications within the genome is a current area of intensive research. A hallmark of these and other DNA repair enzymes is their use of base flipping to sequester modified nucleotides from the DNA helix and into an active site pocket. Consequently, base flipping is generally regarded as an essential aspect of lesion recognition and a necessary precursor to base excision. Here we present the first, to our knowledge, DNA glycosylase mechanism that does not require base flipping for either binding or catalysis. Using the DNA glycosylase AlkD from Bacillus cereus, we crystallographically monitored excision of an alkylpurine substrate as a function of time, and reconstructed the steps along the reaction coordinate through structures representing substrate, intermediate and product complexes. Instead of directly interacting with the damaged nucleobase, AlkD recognizes aberrant base pairs through interactions with the phosphoribose backbone, while the lesion remains stacked in the DNA duplex. Quantum mechanical calculations revealed that these contacts include catalytic charge-dipole and CH-pi interactions that preferentially stabilize the transition state. We show in vitro and in vivo how this unique means of recognition and catalysis enables AlkD to repair large adducts formed by yatakemycin, a member of the duocarmycin family of antimicrobial natural products exploited in bacterial warfare and chemotherapeutic trials. Bulky adducts of this or any type are not excised by DNA glycosylases that use a traditional base-flipping mechanism. Hence, these findings represent a new model for DNA repair and provide insights into catalysis of base excision.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mullins, Elwood A -- Shi, Rongxin -- Parsons, Zachary D -- Yuen, Philip K -- David, Sheila S -- Igarashi, Yasuhiro -- Eichman, Brandt F -- R01 ES019625/ES/NIEHS NIH HHS/ -- R01CA067985/CA/NCI NIH HHS/ -- R01ES019625/ES/NIEHS NIH HHS/ -- S10RR026915/RR/NCRR NIH HHS/ -- T32 ES007028/ES/NIEHS NIH HHS/ -- T32ES07028/ES/NIEHS NIH HHS/ -- England -- Nature. 2015 Nov 12;527(7577):254-8. doi: 10.1038/nature15728. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232, USA. ; Department of Chemistry, University of California, Davis, California 95616, USA. ; Biotechnology Research Center, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524531" target="_blank"〉PubMed〈/a〉
    Keywords: Bacillus cereus/*enzymology ; Base Pairing ; *Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; DNA Adducts/*chemistry/*metabolism ; DNA Damage ; DNA Glycosylases/*chemistry/*metabolism ; *DNA Repair ; Indoles ; Models, Molecular ; Pyrroles
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    Crystal structures of the human adiponectin receptors (2015)
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    Publication Date: 2015-04-10
    Description: Adiponectin stimulation of its receptors, AdipoR1 and AdipoR2, increases the activities of 5' AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR), respectively, thereby contributing to healthy longevity as key anti-diabetic molecules. AdipoR1 and AdipoR2 were predicted to contain seven transmembrane helices with the opposite topology to G-protein-coupled receptors. Here we report the crystal structures of human AdipoR1 and AdipoR2 at 2.9 and 2.4 A resolution, respectively, which represent a novel class of receptor structure. The seven-transmembrane helices, conformationally distinct from those of G-protein-coupled receptors, enclose a large cavity where three conserved histidine residues coordinate a zinc ion. The zinc-binding structure may have a role in the adiponectin-stimulated AMPK phosphorylation and UCP2 upregulation. Adiponectin may broadly interact with the extracellular face, rather than the carboxy-terminal tail, of the receptors. The present information will facilitate the understanding of novel structure-function relationships and the development and optimization of AdipoR agonists for the treatment of obesity-related diseases, such as type 2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477036/" 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/PMC4477036/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tanabe, Hiroaki -- Fujii, Yoshifumi -- Okada-Iwabu, Miki -- Iwabu, Masato -- Nakamura, Yoshihiro -- Hosaka, Toshiaki -- Motoyama, Kanna -- Ikeda, Mariko -- Wakiyama, Motoaki -- Terada, Takaho -- Ohsawa, Noboru -- Hato, Masakatsu -- Ogasawara, Satoshi -- Hino, Tomoya -- Murata, Takeshi -- Iwata, So -- Hirata, Kunio -- Kawano, Yoshiaki -- Yamamoto, Masaki -- Kimura-Someya, Tomomi -- Shirouzu, Mikako -- Yamauchi, Toshimasa -- Kadowaki, Takashi -- Yokoyama, Shigeyuki -- 062164/Z/00/Z/Wellcome Trust/United Kingdom -- 089809/Wellcome Trust/United Kingdom -- BB/G02325/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2015 Apr 16;520(7547):312-6. doi: 10.1038/nature14301. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [4] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ; 1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [3] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan. ; Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. ; 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. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan [4] Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage, Chiba 263-8522, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan [3] JST, Research Acceleration Program, Membrane Protein Crystallography Project, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan [4] Division of Molecular Biosciences, Membrane Protein Crystallography Group, Imperial College, London SW7 2AZ, UK [5] Diamond Light Source, Harwell Science and Innovation Campus, Chilton, Didcot, Oxfordshire OX11 0DE, UK [6] RIKEN SPring-8 Center, Harima Institute, Kouto, Sayo, Hyogo 679-5148, Japan. ; RIKEN SPring-8 Center, Harima Institute, Kouto, Sayo, Hyogo 679-5148, Japan. ; 1] Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [2] Department of Integrated Molecular Science on Metabolic Diseases, 22nd Century Medical and Research Center, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. ; 1] RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan [2] Department of Biophysics and Biochemistry and Laboratory of Structural Biology, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan [3] RIKEN Structural Biology Laboratory, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855295" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Crystallography, X-Ray ; Histidine/chemistry/metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Receptors, Adiponectin/*chemistry/metabolism ; Structure-Activity Relationship ; Zinc/metabolism
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    Atomic structure of the APC/C and its mechanism of protein ubiquitination (2015)
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    Publication Date: 2015-06-18
    Description: The anaphase-promoting complex (APC/C) is a multimeric RING E3 ubiquitin ligase that controls chromosome segregation and mitotic exit. Its regulation by coactivator subunits, phosphorylation, the mitotic checkpoint complex and interphase early mitotic inhibitor 1 (Emi1) ensures the correct order and timing of distinct cell-cycle transitions. Here we use cryo-electron microscopy to determine atomic structures of APC/C-coactivator complexes with either Emi1 or a UbcH10-ubiquitin conjugate. These structures define the architecture of all APC/C subunits, the position of the catalytic module and explain how Emi1 mediates inhibition of the two E2s UbcH10 and Ube2S. Definition of Cdh1 interactions with the APC/C indicates how they are antagonized by Cdh1 phosphorylation. The structure of the APC/C with UbcH10-ubiquitin reveals insights into the initiating ubiquitination reaction. Our results provide a quantitative framework for the design of future experiments to investigate APC/C functions in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608048/" 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/PMC4608048/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chang, Leifu -- Zhang, Ziguo -- Yang, Jing -- McLaughlin, Stephen H -- Barford, David -- A8022/Cancer Research UK/United Kingdom -- MC_UP_1201/6/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2015 Jun 25;522(7557):450-4. doi: 10.1038/nature14471. Epub 2015 Jun 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26083744" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase-Promoting Complex-Cyclosome/chemistry/*metabolism/*ultrastructure ; Apc1 Subunit, Anaphase-Promoting ; Complex-Cyclosome/chemistry/metabolism/ultrastructure ; Apc10 Subunit, Anaphase-Promoting ; Complex-Cyclosome/chemistry/metabolism/ultrastructure ; Apc11 Subunit, Anaphase-Promoting Complex-Cyclosome/chemistry/metabolism ; Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome/chemistry/metabolism ; Apc8 Subunit, Anaphase-Promoting ; Complex-Cyclosome/chemistry/metabolism/ultrastructure ; Cadherins/chemistry/metabolism/ultrastructure ; Catalytic Domain ; Cell Cycle Proteins/chemistry/metabolism/ultrastructure ; Cryoelectron Microscopy ; Cytoskeletal Proteins/chemistry/metabolism ; F-Box Proteins/chemistry/metabolism/ultrastructure ; Humans ; Lysine/metabolism ; Models, Molecular ; Phosphorylation ; Protein Binding ; Protein Subunits/chemistry/metabolism ; Structure-Activity Relationship ; Substrate Specificity ; Ubiquitin/chemistry/metabolism/ultrastructure ; Ubiquitin-Conjugating Enzymes/chemistry/metabolism/ultrastructure ; *Ubiquitination
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    Mechanism of phospho-ubiquitin-induced PARKIN activation (2015)
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    Publication Date: 2015-07-15
    Description: The E3 ubiquitin ligase PARKIN (encoded by PARK2) and the protein kinase PINK1 (encoded by PARK6) are mutated in autosomal-recessive juvenile Parkinsonism (AR-JP) and work together in the disposal of damaged mitochondria by mitophagy. PINK1 is stabilized on the outside of depolarized mitochondria and phosphorylates polyubiquitin as well as the PARKIN ubiquitin-like (Ubl) domain. These phosphorylation events lead to PARKIN recruitment to mitochondria, and activation by an unknown allosteric mechanism. Here we present the crystal structure of Pediculus humanus PARKIN in complex with Ser65-phosphorylated ubiquitin (phosphoUb), revealing the molecular basis for PARKIN recruitment and activation. The phosphoUb binding site on PARKIN comprises a conserved phosphate pocket and harbours residues mutated in patients with AR-JP. PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN. Moreover, phosphoUb-mediated Ubl release enhances Ubl phosphorylation by PINK1, leading to conformational changes within the Ubl domain and stabilization of an open, active conformation of PARKIN. We redefine the role of the Ubl domain not only as an inhibitory but also as an activating element that is restrained in inactive PARKIN and released by phosphoUb. Our work opens up new avenues to identify small-molecule PARKIN activators.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wauer, Tobias -- Simicek, Michal -- Schubert, Alexander -- Komander, David -- U105192732/Medical Research Council/United Kingdom -- England -- Nature. 2015 Aug 20;524(7565):370-4. doi: 10.1038/nature14879. Epub 2015 Jul 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26161729" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites/genetics ; Conserved Sequence/genetics ; Crystallography, X-Ray ; Enzyme Activation ; Humans ; Models, Molecular ; Mutation/genetics ; Parkinsonian Disorders/genetics ; Pediculus/*chemistry ; Phosphates/metabolism ; Phosphoproteins/chemistry/metabolism ; Phosphorylation ; Protein Binding ; Protein Kinases/metabolism ; Protein Structure, Tertiary ; Structure-Activity Relationship ; Ubiquitin/*chemistry/*metabolism ; Ubiquitin-Protein Ligases/*chemistry/genetics/*metabolism
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    The octahaem MccA is a haem c-copper sulfite reductase (2015)
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    Publication Date: 2015-02-03
    Description: The six-electron reduction of sulfite to sulfide is the pivot point of the biogeochemical cycle of the element sulfur. The octahaem cytochrome c MccA (also known as SirA) catalyses this reaction for dissimilatory sulfite utilization by various bacteria. It is distinct from known sulfite reductases because it has a substantially higher catalytic activity and a relatively low reactivity towards nitrite. The mechanistic reasons for the increased efficiency of MccA remain to be elucidated. Here we show that anoxically purified MccA exhibited a 2- to 5.5-fold higher specific sulfite reductase activity than the enzyme isolated under oxic conditions. We determined the three-dimensional structure of MccA to 2.2 A resolution by single-wavelength anomalous dispersion. We find a homotrimer with an unprecedented fold and haem arrangement, as well as a haem bound to a CX15CH motif. The heterobimetallic active-site haem 2 has a Cu(I) ion juxtaposed to a haem c at a Fe-Cu distance of 4.4 A. While the combination of metals is reminiscent of respiratory haem-copper oxidases, the oxidation-labile Cu(I) centre of MccA did not seem to undergo a redox transition during catalysis. Intact MccA tightly bound SO2 at haem 2, a dehydration product of the substrate sulfite that was partially turned over due to photoreduction by X-ray irradiation, yielding the reaction intermediate SO. Our data show the biometal copper in a new context and function and provide a chemical rationale for the comparatively high catalytic activity of MccA.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hermann, Bianca -- Kern, Melanie -- La Pietra, Luigi -- Simon, Jorg -- Einsle, Oliver -- England -- Nature. 2015 Apr 30;520(7549):706-9. doi: 10.1038/nature14109. Epub 2015 Feb 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lehrstuhl Biochemie, Institut fur Biochemie, Albert-Ludwigs-Universitat Freiburg, Albertstrasse 21, 79104 Freiburg, Germany. ; Microbial Energy Conversion &Biotechnology, Department of Biology, Technische Universitat Darmstadt, Schnittspahnstrasse 10, 64287 Darmstadt, Germany. ; 1] Lehrstuhl Biochemie, Institut fur Biochemie, Albert-Ludwigs-Universitat Freiburg, Albertstrasse 21, 79104 Freiburg, Germany [2] BIOSS Centre for Biological Signalling Studies, Schanzlestrasse 1, 79104 Freiburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25642962" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/isolation & purification/metabolism ; Biocatalysis ; Catalytic Domain ; Copper/*metabolism ; Crystallography, X-Ray ; Cysteine/analogs & derivatives/metabolism ; Heme/*analogs & derivatives/metabolism ; Models, Molecular ; Oxidation-Reduction ; Oxidoreductases Acting on Sulfur Group Donors/*chemistry/isolation & ; purification/metabolism ; Sulfites/metabolism ; Sulfur Dioxide/metabolism ; Wolinella/*enzymology
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    Structure of the E. coli ribosome-EF-Tu complex at 〈3 A resolution by Cs-corrected cryo-EM (2015)
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    Publication Date: 2015-02-25
    Description: Single particle electron cryomicroscopy (cryo-EM) has recently made significant progress in high-resolution structure determination of macromolecular complexes due to improvements in electron microscopic instrumentation and computational image analysis. However, cryo-EM structures can be highly non-uniform in local resolution and all structures available to date have been limited to resolutions above 3 A. Here we present the cryo-EM structure of the 70S ribosome from Escherichia coli in complex with elongation factor Tu, aminoacyl-tRNA and the antibiotic kirromycin at 2.65-2.9 A resolution using spherical aberration (Cs)-corrected cryo-EM. Overall, the cryo-EM reconstruction at 2.9 A resolution is comparable to the best-resolved X-ray structure of the E. coli 70S ribosome (2.8 A), but provides more detailed information (2.65 A) at the functionally important ribosomal core. The cryo-EM map elucidates for the first time the structure of all 35 rRNA modifications in the bacterial ribosome, explaining their roles in fine-tuning ribosome structure and function and modulating the action of antibiotics. We also obtained atomic models for flexible parts of the ribosome such as ribosomal proteins L9 and L31. The refined cryo-EM-based model presents the currently most complete high-resolution structure of the E. coli ribosome, which demonstrates the power of cryo-EM in structure determination of large and dynamic macromolecular complexes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fischer, Niels -- Neumann, Piotr -- Konevega, Andrey L -- Bock, Lars V -- Ficner, Ralf -- Rodnina, Marina V -- Stark, Holger -- England -- Nature. 2015 Apr 23;520(7548):567-70. doi: 10.1038/nature14275. Epub 2015 Feb 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉3D Electron Cryomicroscopy Group, Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany. ; Abteilung Molekulare Strukturbiologie, Institut fur Mikrobiologie und Genetik, GZMB, Georg-August Universitat Gottingen, Justus-von Liebig Weg 11, 37077 Gottingen, Germany. ; 1] Molecular and Radiation Biophysics Department, B.P. Konstantinov Petersburg Nuclear Physics Institute of National Research Centre 'Kurchatov Institute', 188300 Gatchina, Russia [2] St Petersburg Polytechnic University, Polytechnicheskaya, 29, 195251 St Petersburg, Russia [3] Department of Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany. ; Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany. ; Department of Physical Biochemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany. ; 1] 3D Electron Cryomicroscopy Group, Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany [2] Department of 3D Electron Cryomicroscopy, Institute of Microbiology and Genetics, Georg-August Universitat, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707802" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/chemistry/metabolism ; *Cryoelectron Microscopy/methods ; Escherichia coli/*chemistry/*ultrastructure ; Ligands ; Models, Molecular ; Peptide Elongation Factor Tu/*chemistry/metabolism/*ultrastructure ; Pyridones/chemistry/metabolism ; RNA, Bacterial/chemistry/metabolism/ultrastructure ; RNA, Ribosomal/chemistry/metabolism/ultrastructure ; RNA, Transfer/chemistry/metabolism/ultrastructure ; Ribosomes/*chemistry/metabolism/*ultrastructure
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    Universal allosteric mechanism for Galpha activation by GPCRs (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-07-07
    Description: G protein-coupled receptors (GPCRs) allosterically activate heterotrimeric G proteins and trigger GDP release. Given that there are approximately 800 human GPCRs and 16 different Galpha genes, this raises the question of whether a universal allosteric mechanism governs Galpha activation. Here we show that different GPCRs interact with and activate Galpha proteins through a highly conserved mechanism. Comparison of Galpha with the small G protein Ras reveals how the evolution of short segments that undergo disorder-to-order transitions can decouple regions important for allosteric activation from receptor binding specificity. This might explain how the GPCR-Galpha system diversified rapidly, while conserving the allosteric activation mechanism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Flock, Tilman -- Ravarani, Charles N J -- Sun, Dawei -- Venkatakrishnan, A J -- Kayikci, Melis -- Tate, Christopher G -- Veprintsev, Dmitry B -- Babu, M Madan -- MC_U105185859/Medical Research Council/United Kingdom -- MC_U105197215/Medical Research Council/United Kingdom -- England -- Nature. 2015 Aug 13;524(7564):173-9. doi: 10.1038/nature14663. Epub 2015 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. ; 1] Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen, Switzerland [2] Department of Biology, ETH Zurich, 8039 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26147082" target="_blank"〉PubMed〈/a〉
    Keywords: *Allosteric Regulation ; Animals ; Binding Sites ; Computational Biology ; Conserved Sequence ; Enzyme Activation ; *Evolution, Molecular ; GTP-Binding Protein alpha Subunits/chemistry/genetics/*metabolism ; Genetic Engineering ; Guanosine Diphosphate/metabolism ; Humans ; Models, Molecular ; Mutation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/chemistry/*metabolism ; Signal Transduction ; Substrate Specificity ; ras Proteins/chemistry/metabolism
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    A novel multiple-stage antimalarial agent that inhibits protein synthesis (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-06-19
    Description: There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700930/" 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/PMC4700930/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baragana, Beatriz -- Hallyburton, Irene -- Lee, Marcus C S -- Norcross, Neil R -- Grimaldi, Raffaella -- Otto, Thomas D -- Proto, William R -- Blagborough, Andrew M -- Meister, Stephan -- Wirjanata, Grennady -- Ruecker, Andrea -- Upton, Leanna M -- Abraham, Tara S -- Almeida, Mariana J -- Pradhan, Anupam -- Porzelle, Achim -- Martinez, Maria Santos -- Bolscher, Judith M -- Woodland, Andrew -- Norval, Suzanne -- Zuccotto, Fabio -- Thomas, John -- Simeons, Frederick -- Stojanovski, Laste -- Osuna-Cabello, Maria -- Brock, Paddy M -- Churcher, Tom S -- Sala, Katarzyna A -- Zakutansky, Sara E -- Jimenez-Diaz, Maria Belen -- Sanz, Laura Maria -- Riley, Jennifer -- Basak, Rajshekhar -- Campbell, Michael -- Avery, Vicky M -- Sauerwein, Robert W -- Dechering, Koen J -- Noviyanti, Rintis -- Campo, Brice -- Frearson, Julie A -- Angulo-Barturen, Inigo -- Ferrer-Bazaga, Santiago -- Gamo, Francisco Javier -- Wyatt, Paul G -- Leroy, Didier -- Siegl, Peter -- Delves, Michael J -- Kyle, Dennis E -- Wittlin, Sergio -- Marfurt, Jutta -- Price, Ric N -- Sinden, Robert E -- Winzeler, Elizabeth A -- Charman, Susan A -- Bebrevska, Lidiya -- Gray, David W -- Campbell, Simon -- Fairlamb, Alan H -- Willis, Paul A -- Rayner, Julian C -- Fidock, David A -- Read, Kevin D -- Gilbert, Ian H -- 079838/Wellcome Trust/United Kingdom -- 091625/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 100476/Wellcome Trust/United Kingdom -- R01 AI090141/AI/NIAID NIH HHS/ -- R01 AI103058/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Jun 18;522(7556):315-20. doi: 10.1038/nature14451.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. ; Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. ; Malaria Programme, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK. ; Department of Life Sciences, Imperial College, London SW7 2AZ, UK. ; University of California, San Diego, School of Medicine, 9500 Gilman Drive 0760, La Jolla, California 92093, USA. ; Global Health and Tropical Medicine Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia. ; Department of Global Health, College of Public Health University of South Florida, 3720 Spectrum Boulevard, Suite 304, Tampa, Florida 33612, USA. ; GlaxoSmithKline, Tres Cantos Medicines Development Campus-Diseases of the Developing World, Severo Ochoa 2, Tres Cantos 28760, Madrid, Spain. ; TropIQ Health Sciences, Geert Grooteplein 28, Huispost 268, 6525 GA Nijmegen, The Netherlands. ; Centre for Drug Candidate Optimisation, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia. ; Eskitis Institute, Brisbane Innovation Park, Nathan Campus, Griffith University, Queensland 4111, Australia. ; Malaria Pathogenesis Laboratory, Eijkman Institute for Molecular Biology, Jalan Diponegoro 69, 10430 Jakarta, Indonesia. ; Medicines for Malaria Venture, PO Box 1826, 20 route de Pre-Bois, 1215 Geneva 15, Switzerland. ; Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland. ; 1] Global Health and Tropical Medicine Division, Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, Darwin, Northern Territory 0811, Australia [2] Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LJ, UK. ; 1] Department of Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA [2] Division of Infectious Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26085270" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antimalarials/administration & dosage/adverse ; effects/pharmacokinetics/*pharmacology ; Drug Discovery ; Female ; Gene Expression Regulation/*drug effects ; Life Cycle Stages/drug effects ; Liver/drug effects/parasitology ; Malaria/drug therapy/*parasitology ; Male ; Models, Molecular ; Peptide Elongation Factor 2/antagonists & inhibitors/metabolism ; Plasmodium/*drug effects/genetics/growth & development/*metabolism ; Plasmodium berghei/drug effects/physiology ; Plasmodium falciparum/drug effects/metabolism ; Plasmodium vivax/drug effects/metabolism ; Protein Biosynthesis/*drug effects ; Quinolines/administration & dosage/chemistry/pharmacokinetics/*pharmacology
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    First biosimilar drug set to enter US market (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-01-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ledford, Heidi -- England -- Nature. 2015 Jan 15;517(7534):253-4. doi: 10.1038/517253a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25592512" target="_blank"〉PubMed〈/a〉
    Keywords: Antibodies, Monoclonal, Humanized/economics ; Bevacizumab ; Biosimilar Pharmaceuticals/chemistry/*economics/*supply & ; distribution/therapeutic use ; Drug Industry/economics/legislation & jurisprudence ; Drugs, Generic/economics ; Filgrastim ; Granulocyte Colony-Stimulating Factor/chemistry/economics/supply & ; distribution/therapeutic use ; Humans ; Models, Molecular ; Neoplasms/drug therapy ; Patents as Topic/legislation & jurisprudence ; Recombinant Proteins/chemistry/economics/supply & distribution/therapeutic use ; Uncertainty ; United States ; United States Food and Drug Administration/*legislation & jurisprudence
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    Computational design of co-assembling protein-DNA nanowires (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-09-04
    Description: Biomolecular self-assemblies are of great interest to nanotechnologists because of their functional versatility and their biocompatibility. Over the past decade, sophisticated single-component nanostructures composed exclusively of nucleic acids, peptides and proteins have been reported, and these nanostructures have been used in a wide range of applications, from drug delivery to molecular computing. Despite these successes, the development of hybrid co-assemblies of nucleic acids and proteins has remained elusive. Here we use computational protein design to create a protein-DNA co-assembling nanomaterial whose assembly is driven via non-covalent interactions. To achieve this, a homodimerization interface is engineered onto the Drosophila Engrailed homeodomain (ENH), allowing the dimerized protein complex to bind to two double-stranded DNA (dsDNA) molecules. By varying the arrangement of protein-binding sites on the dsDNA, an irregular bulk nanoparticle or a nanowire with single-molecule width can be spontaneously formed by mixing the protein and dsDNA building blocks. We characterize the protein-DNA nanowire using fluorescence microscopy, atomic force microscopy and X-ray crystallography, confirming that the nanowire is formed via the proposed mechanism. This work lays the foundation for the development of new classes of protein-DNA hybrid materials. Further applications can be explored by incorporating DNA origami, DNA aptamers and/or peptide epitopes into the protein-DNA framework presented here.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mou, Yun -- Yu, Jiun-Yann -- Wannier, Timothy M -- Guo, Chin-Lin -- Mayo, Stephen L -- England -- Nature. 2015 Sep 10;525(7568):230-3. doi: 10.1038/nature14874. Epub 2015 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA. ; Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26331548" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; *Computer Simulation ; Crystallization ; Crystallography, X-Ray ; DNA/*chemistry ; *Drug Design ; Homeodomain Proteins/chemistry/genetics/metabolism ; Microscopy, Atomic Force ; Microscopy, Fluorescence ; Models, Molecular ; Nanotechnology ; Nanowires/*chemistry ; Protein Multimerization ; Transcription Factors/chemistry/genetics/metabolism
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    PROTEIN STRUCTURE. Crystal structure of a mycobacterial Insig homolog provides insight into how these sensors monitor sterol levels (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-07-15
    Description: Insulin-induced gene 1 (Insig-1) and Insig-2 are endoplasmic reticulum membrane-embedded sterol sensors that regulate the cellular accumulation of sterols. Despite their physiological importance, the structural information on Insigs remains limited. Here we report the high-resolution structures of MvINS, an Insig homolog from Mycobacterium vanbaalenii. MvINS exists as a homotrimer. Each protomer comprises six transmembrane segments (TMs), with TM3 and TM4 contributing to homotrimerization. The six TMs enclose a V-shaped cavity that can accommodate a diacylglycerol molecule. A homology-based structural model of human Insig-2, together with biochemical characterizations, suggest that the central cavity of Insig-2 accommodates 25-hydroxycholesterol, whereas TM3 and TM4 engage in Scap binding. These analyses provide an important framework for further functional and mechanistic understanding of Insig proteins and the sterol regulatory element-binding protein pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704858/" 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/PMC4704858/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ren, Ruobing -- Zhou, Xinhui -- He, Yuan -- Ke, Meng -- Wu, Jianping -- Liu, Xiaohui -- Yan, Chuangye -- Wu, Yixuan -- Gong, Xin -- Lei, Xiaoguang -- Yan, S Frank -- Radhakrishnan, Arun -- Yan, Nieng -- HL-20948/HL/NHLBI NIH HHS/ -- P01 HL020948/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jul 10;349(6244):187-91. doi: 10.1126/science.aab1091.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China. Center for Structural Biology, School of Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China. ; National Institute of Biological Sciences, Beijing 102206, China. ; Molecular Design and Chemical Biology, Therapeutic Modalities, Roche Pharma Research and Early Development, Roche Innovation Center Shanghai, Shanghai 201203, China. ; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26160948" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry ; Crystallography, X-Ray ; Diglycerides/chemistry ; Humans ; Hydroxycholesterols/chemistry/*metabolism ; Intracellular Signaling Peptides and Proteins/*chemistry ; Membrane Proteins/*chemistry ; Mycobacterium/*metabolism ; Protein Multimerization ; Protein Structure, Secondary ; Sterol Regulatory Element Binding Proteins/*chemistry
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    Structural biology. Mechanistic insight from the crystal structure of mitochondrial complex I (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-01-03
    Description: Proton-pumping complex I of the mitochondrial respiratory chain is among the largest and most complicated membrane protein complexes. The enzyme contributes substantially to oxidative energy conversion in eukaryotic cells. Its malfunctions are implicated in many hereditary and degenerative disorders. We report the x-ray structure of mitochondrial complex I at a resolution of 3.6 to 3.9 angstroms, describing in detail the central subunits that execute the bioenergetic function. A continuous axis of basic and acidic residues running centrally through the membrane arm connects the ubiquinone reduction site in the hydrophilic arm to four putative proton-pumping units. The binding position for a substrate analogous inhibitor and blockage of the predicted ubiquinone binding site provide a model for the "deactive" form of the enzyme. The proposed transition into the active form is based on a concerted structural rearrangement at the ubiquinone reduction site, providing support for a two-state stabilization-change mechanism of proton pumping.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zickermann, Volker -- Wirth, Christophe -- Nasiri, Hamid -- Siegmund, Karin -- Schwalbe, Harald -- Hunte, Carola -- Brandt, Ulrich -- New York, N.Y. -- Science. 2015 Jan 2;347(6217):44-9. doi: 10.1126/science.1259859.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Bioenergetics Group, Institute of Biochemistry II, Medical School, Goethe-University, 60438 Frankfurt am Main, Germany. Cluster of Excellence Frankfurt "Macromolecular Complexes," Goethe-University, 60438 Frankfurt am Main, Germany. zickermann@med.uni-frankfurt.de carola.hunte@biochemie.uni-freiburg.de ulrich.brandt@radboudumc.nl. ; Institute for Biochemistry and Molecular Biology, ZBMZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany. ; Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK. Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, 60438 Frankfurt am Main, Germany. ; Structural Bioenergetics Group, Institute of Biochemistry II, Medical School, Goethe-University, 60438 Frankfurt am Main, Germany. ; Cluster of Excellence Frankfurt "Macromolecular Complexes," Goethe-University, 60438 Frankfurt am Main, Germany. Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, 60438 Frankfurt am Main, Germany. ; Institute for Biochemistry and Molecular Biology, ZBMZ, BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany. zickermann@med.uni-frankfurt.de carola.hunte@biochemie.uni-freiburg.de ulrich.brandt@radboudumc.nl. ; Cluster of Excellence Frankfurt "Macromolecular Complexes," Goethe-University, 60438 Frankfurt am Main, Germany. Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. zickermann@med.uni-frankfurt.de carola.hunte@biochemie.uni-freiburg.de ulrich.brandt@radboudumc.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25554780" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Electron Transport Complex I/*chemistry/ultrastructure ; Mitochondria/*enzymology ; Mitochondrial Membranes/*enzymology ; Protein Structure, Secondary ; Protons ; Ubiquinone/chemistry ; Yarrowia/enzymology
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    METALLOPROTEINS. A tethered niacin-derived pincer complex with a nickel-carbon bond in lactate racemase (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-07-04
    Description: Lactic acid racemization is involved in lactate metabolism and cell wall assembly of many microorganisms. Lactate racemase (Lar) requires nickel, but the nickel-binding site and the role of three accessory proteins required for its activation remain enigmatic. We combined mass spectrometry and x-ray crystallography to show that Lar from Lactobacillus plantarum possesses an organometallic nickel-containing prosthetic group. A nicotinic acid mononucleotide derivative is tethered to Lys(184) and forms a tridentate pincer complex that coordinates nickel through one metal-carbon and two metal-sulfur bonds, with His(200) as another ligand. Although similar complexes have been previously synthesized, there was no prior evidence for the existence of pincer cofactors in enzymes. The wide distribution of the accessory proteins without Lar suggests that it may play a role in other enzymes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Desguin, Benoit -- Zhang, Tuo -- Soumillion, Patrice -- Hols, Pascal -- Hu, Jian -- Hausinger, Robert P -- New York, N.Y. -- Science. 2015 Jul 3;349(6243):66-9. doi: 10.1126/science.aab2272.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA. ; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. ; Institute of Life Sciences, Universite Catholique de Louvain, B-1348 Louvain-la-Neuve, Belgium. ; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA. hujian1@msu.edu hausinge@msu.edu. ; Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. hujian1@msu.edu hausinge@msu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26138974" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/genetics ; Binding Sites ; Carbon/chemistry ; Catalysis ; Crystallography, X-Ray ; Histidine/chemistry ; Holoenzymes/chemistry ; Lactic Acid/*biosynthesis/chemistry ; Lactobacillus plantarum/*enzymology/genetics ; Ligands ; Lysine/chemistry ; Metalloproteins/*chemistry/genetics ; Niacin/*chemistry ; Nickel/*chemistry ; Nicotinamide Mononucleotide/analogs & derivatives/chemistry ; Protein Processing, Post-Translational ; Protein Structure, Secondary ; Racemases and Epimerases/*chemistry/genetics ; Spectrometry, Mass, Electrospray Ionization ; Sulfur
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    K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-03-15
    Description: TREK-2 (KCNK10/K2P10), a two-pore domain potassium (K2P) channel, is gated by multiple stimuli such as stretch, fatty acids, and pH and by several drugs. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. These results provide an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, Yin Yao -- Pike, Ashley C W -- Mackenzie, Alexandra -- McClenaghan, Conor -- Aryal, Prafulla -- Dong, Liang -- Quigley, Andrew -- Grieben, Mariana -- Goubin, Solenne -- Mukhopadhyay, Shubhashish -- Ruda, Gian Filippo -- Clausen, Michael V -- Cao, Lishuang -- Brennan, Paul E -- Burgess-Brown, Nicola A -- Sansom, Mark S P -- Tucker, Stephen J -- Carpenter, Elisabeth P -- 084655/Wellcome Trust/United Kingdom -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Mar 13;347(6227):1256-9. doi: 10.1126/science.1261512.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. ; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. ; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. ; Pfizer Neusentis, Granta Park, Cambridge CB21 6GS, UK. ; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. liz.carpenter@sgc.ox.ac.uk stephen.tucker@physics.ox.ac.uk. ; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. liz.carpenter@sgc.ox.ac.uk stephen.tucker@physics.ox.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25766236" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arachidonic Acid/pharmacology ; Binding Sites ; Crystallography, X-Ray ; Fluoxetine/analogs & derivatives/chemistry/metabolism/pharmacology ; Humans ; *Ion Channel Gating ; Models, Molecular ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Potassium/metabolism ; Potassium Channels, Tandem Pore Domain/antagonists & ; inhibitors/*chemistry/metabolism ; Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary
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    Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-10-10
    Description: Phosphatidylinositol 3-kinase Vps34 complexes regulate intracellular membrane trafficking in endocytic sorting, cytokinesis, and autophagy. We present the 4.4 angstrom crystal structure of the 385-kilodalton endosomal complex II (PIK3C3-CII), consisting of Vps34, Vps15 (p150), Vps30/Atg6 (Beclin 1), and Vps38 (UVRAG). The subunits form a Y-shaped complex, centered on the Vps34 C2 domain. Vps34 and Vps15 intertwine in one arm, where the Vps15 kinase domain engages the Vps34 activation loop to regulate its activity. Vps30 and Vps38 form the other arm that brackets the Vps15/Vps34 heterodimer, suggesting a path for complex assembly. We used hydrogen-deuterium exchange mass spectrometry (HDX-MS) to reveal conformational changes accompanying membrane binding and identify a Vps30 loop that is critical for the ability of complex II to phosphorylate giant liposomes on which complex I is inactive.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4601532/" 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/PMC4601532/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rostislavleva, Ksenia -- Soler, Nicolas -- Ohashi, Yohei -- Zhang, Lufei -- Pardon, Els -- Burke, John E -- Masson, Glenn R -- Johnson, Chris -- Steyaert, Jan -- Ktistakis, Nicholas T -- Williams, Roger L -- BB/K019155/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MC_U105184308/Medical Research Council/United Kingdom -- PG11/109/29247/British Heart Foundation/United Kingdom -- U105184308/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Oct 9;350(6257):aac7365. doi: 10.1126/science.aac7365.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. ; Structural Biology Research Center, VIB, B-1050 Brussels, Belgium. Structural Biology Brussels, Vrije Universiteit Brussel, B-1050 Brussels, Belgium. ; The Babraham Institute, Cambridge, UK. ; Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge CB2 0QH, UK. rlw@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26450213" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Membrane/chemistry/*enzymology ; Class III Phosphatidylinositol 3-Kinases/chemistry/*ultrastructure ; Crystallography, X-Ray ; Endosomes/chemistry/*enzymology ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/enzymology ; Vacuolar Sorting Protein VPS15/chemistry/ultrastructure
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    INTRACELLULAR TRANSPORT. Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4-phosphate (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-07-25
    Description: In eukaryotic cells, phosphatidylserine (PS) is synthesized in the endoplasmic reticulum (ER) but is highly enriched in the plasma membrane (PM), where it contributes negative charge and to specific recruitment of signaling proteins. This distribution relies on transport mechanisms whose nature remains elusive. Here, we found that the PS transporter Osh6p extracted phosphatidylinositol 4-phosphate (PI4P) and exchanged PS for PI4P between two membranes. We solved the crystal structure of Osh6p:PI4P complex and demonstrated that the transport of PS by Osh6p depends on PI4P recognition in vivo. Finally, we showed that the PI4P-phosphatase Sac1p, by maintaining a PI4P gradient at the ER/PM interface, drove PS transport. Thus, PS transport by oxysterol-binding protein-related protein (ORP)/oxysterol-binding homology (Osh) proteins is fueled by PI4P metabolism through PS/PI4P exchange cycles.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moser von Filseck, Joachim -- Copic, Alenka -- Delfosse, Vanessa -- Vanni, Stefano -- Jackson, Catherine L -- Bourguet, William -- Drin, Guillaume -- New York, N.Y. -- Science. 2015 Jul 24;349(6246):432-6. doi: 10.1126/science.aab1346. Epub 2015 Jul 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Pharmacologie Moleculaire et Cellulaire, Universite de Nice Sophia-Antipolis and CNRS, 660 route des lucioles, 06560 Valbonne, France. ; Institut Jacques Monod, CNRS, UMR 7592, Universite Paris Diderot, Sorbonne Paris Cite, F-75013 Paris, France. ; Inserm U1054, 29 rue de Navacelles, 34090 Montpellier, France. CNRS UMR5048, Centre de Biochimie Structurale, 29 rue de Navacelles, 34090 Montpellier, France. ; Institut de Pharmacologie Moleculaire et Cellulaire, Universite de Nice Sophia-Antipolis and CNRS, 660 route des lucioles, 06560 Valbonne, France. drin@ipmc.cnrs.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26206936" target="_blank"〉PubMed〈/a〉
    Keywords: Biological Transport ; Cell Membrane/*metabolism ; Crystallography, X-Ray ; Endoplasmic Reticulum/*metabolism ; Phosphatidylinositol Phosphates/chemistry/*metabolism ; Phosphatidylserines/chemistry/*metabolism ; Phosphoric Monoester Hydrolases/genetics/*metabolism ; Receptors, Steroid/chemistry/genetics/*metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/genetics/*metabolism
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    A protein trisulfide couples dissimilatory sulfate reduction to energy conservation (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-12-19
    Description: Microbial sulfate reduction has governed Earth's biogeochemical sulfur cycle for at least 2.5 billion years. However, the enzymatic mechanisms behind this pathway are incompletely understood, particularly for the reduction of sulfite-a key intermediate in the pathway. This critical reaction is performed by DsrAB, a widespread enzyme also involved in other dissimilatory sulfur metabolisms. Using in vitro assays with an archaeal DsrAB, supported with genetic experiments in a bacterial system, we show that the product of sulfite reduction by DsrAB is a protein-based trisulfide, in which a sulfite-derived sulfur is bridging two conserved cysteines of DsrC. Physiological studies also reveal that sulfate reduction rates are determined by cellular levels of DsrC. Dissimilatory sulfate reduction couples the four-electron reduction of the DsrC trisulfide to energy conservation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Santos, Andre A -- Venceslau, Sofia S -- Grein, Fabian -- Leavitt, William D -- Dahl, Christiane -- Johnston, David T -- Pereira, Ines A C -- New York, N.Y. -- Science. 2015 Dec 18;350(6267):1541-5. doi: 10.1126/science.aad3558.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Instituto de Tecnologia Quimica e Biologica Antonio Xavier, Universidade Nova de Lisboa, Oeiras, Portugal. ; Department of Earth and Planetary Science, Harvard University, Cambridge, MA, USA. ; Institut fur Mikrobiologie & Biotechnologie, Rheinische Friedrich-Wilhelms-Universitat Bonn, Germany. ; Instituto de Tecnologia Quimica e Biologica Antonio Xavier, Universidade Nova de Lisboa, Oeiras, Portugal. ipereira@itqb.unl.pt.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26680199" target="_blank"〉PubMed〈/a〉
    Keywords: Archaeal Proteins/chemistry/*metabolism ; Archaeoglobus fulgidus/*enzymology ; Crystallography, X-Ray ; Cysteine/chemistry/metabolism ; *Energy Metabolism ; Oxidation-Reduction ; Proteins/metabolism ; Sulfates/metabolism ; Sulfides/chemistry/*metabolism ; Sulfites/metabolism ; Sulfur/*metabolism
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    Structural biology. Structural basis for chemokine recognition and activation of a viral G protein-coupled receptor (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-03-07
    Description: Chemokines are small proteins that function as immune modulators through activation of chemokine G protein-coupled receptors (GPCRs). Several viruses also encode chemokines and chemokine receptors to subvert the host immune response. How protein ligands activate GPCRs remains unknown. We report the crystal structure at 2.9 angstrom resolution of the human cytomegalovirus GPCR US28 in complex with the chemokine domain of human CX3CL1 (fractalkine). The globular body of CX3CL1 is perched on top of the US28 extracellular vestibule, whereas its amino terminus projects into the central core of US28. The transmembrane helices of US28 adopt an active-state-like conformation. Atomic-level simulations suggest that the agonist-independent activity of US28 may be due to an amino acid network evolved in the viral GPCR to destabilize the receptor's inactive state.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445376/" 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/PMC4445376/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burg, John S -- Ingram, Jessica R -- Venkatakrishnan, A J -- Jude, Kevin M -- Dukkipati, Abhiram -- Feinberg, Evan N -- Angelini, Alessandro -- Waghray, Deepa -- Dror, Ron O -- Ploegh, Hidde L -- Garcia, K Christopher -- DP1 GM106409/GM/NIGMS NIH HHS/ -- R01 GM097015/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Mar 6;347(6226):1113-7. doi: 10.1126/science.aaa5026.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Computer Science, Stanford University, Stanford, CA 94305, USA. Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA. ; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. kcgarcia@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25745166" target="_blank"〉PubMed〈/a〉
    Keywords: CCR5 Receptor Antagonists/chemistry ; Chemokine CX3CL1/*chemistry ; Crystallography, X-Ray ; Cyclohexanes/chemistry ; Humans ; Ligands ; Piperidines/chemistry ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, CXCR4/antagonists & inhibitors ; Receptors, Chemokine/agonists/*chemistry ; Triazoles/chemistry ; Viral Proteins/agonists/*chemistry
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    Structural biology. Division of labor in transhydrogenase by alternating proton translocation and hydride transfer (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-01-13
    Description: NADPH/NADP(+) (the reduced form of NADP(+)/nicotinamide adenine dinucleotide phosphate) homeostasis is critical for countering oxidative stress in cells. Nicotinamide nucleotide transhydrogenase (TH), a membrane enzyme present in both bacteria and mitochondria, couples the proton motive force to the generation of NADPH. We present the 2.8 A crystal structure of the transmembrane proton channel domain of TH from Thermus thermophilus and the 6.9 A crystal structure of the entire enzyme (holo-TH). The membrane domain crystallized as a symmetric dimer, with each protomer containing a putative proton channel. The holo-TH is a highly asymmetric dimer with the NADP(H)-binding domain (dIII) in two different orientations. This unusual arrangement suggests a catalytic mechanism in which the two copies of dIII alternatively function in proton translocation and hydride transfer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479213/" 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/PMC4479213/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leung, Josephine H -- Schurig-Briccio, Lici A -- Yamaguchi, Mutsuo -- Moeller, Arne -- Speir, Jeffrey A -- Gennis, Robert B -- Stout, Charles D -- 1R01GM103838-01A1/GM/NIGMS NIH HHS/ -- 5R01GM061545/GM/NIGMS NIH HHS/ -- GM073197/GM/NIGMS NIH HHS/ -- GM095600/GM/NIGMS NIH HHS/ -- P41 GM103310/GM/NIGMS NIH HHS/ -- P41GM103310/GM/NIGMS NIH HHS/ -- R01 GM061545/GM/NIGMS NIH HHS/ -- R01 GM095600/GM/NIGMS NIH HHS/ -- R01 GM103838/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 9;347(6218):178-81. doi: 10.1126/science.1260451.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Biochemistry, University of Illinois, Urbana, IL 61801, USA. ; National Resource for Automated Molecular Microscopy, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. dave@scripps.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25574024" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Crystallography, X-Ray ; Molecular Sequence Data ; NADP Transhydrogenases/*chemistry ; Protein Multimerization ; Protein Structure, Tertiary ; *Protons ; Thermus thermophilus/enzymology
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    PHOTOSYNTHESIS. A 12 A carotenoid translocation in a photoswitch associated with cyanobacterial photoprotection (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-06-27
    Description: Pigment-protein and pigment-pigment interactions are of fundamental importance to the light-harvesting and photoprotective functions essential to oxygenic photosynthesis. The orange carotenoid protein (OCP) functions as both a sensor of light and effector of photoprotective energy dissipation in cyanobacteria. We report the atomic-resolution structure of an active form of the OCP consisting of the N-terminal domain and a single noncovalently bound carotenoid pigment. The crystal structure, combined with additional solution-state structural data, reveals that OCP photoactivation is accompanied by a 12 angstrom translocation of the pigment within the protein and a reconfiguration of carotenoid-protein interactions. Our results identify the origin of the photochromic changes in the OCP triggered by light and reveal the structural determinants required for interaction with the light-harvesting antenna during photoprotection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leverenz, Ryan L -- Sutter, Markus -- Wilson, Adjele -- Gupta, Sayan -- Thurotte, Adrien -- Bourcier de Carbon, Celine -- Petzold, Christopher J -- Ralston, Corie -- Perreau, Francois -- Kirilovsky, Diana -- Kerfeld, Cheryl A -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jun 26;348(6242):1463-6. doi: 10.1126/science.aaa7234.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MSU-DOE Plant Research Laboratory, Michigan State University, East Lansing, MI 48824, USA. ; MSU-DOE Plant Research Laboratory, Michigan State University, East Lansing, MI 48824, USA. Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. ; Commissariat a l'Energie Atomique (CEA), Institut de Biologie et Technologies de Saclay (iBiTec-S), 91191 Gif-sur-Yvette, France. Centre National de la Recherche Scientifique (CNRS), I2BC, UMR 9198, 91191 Gif-sur-Yvette, France. ; Berkeley Center for Structural Biology, Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. ; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. ; INRA, Institut Jean-Pierre Bourgin, UMR 1318, ERL CNRS 3559, Saclay Plant Sciences, RD10, F-78026 Versailles, France. ; MSU-DOE Plant Research Laboratory, Michigan State University, East Lansing, MI 48824, USA. Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Department of Plant and Microbial Biology, University of California, Berkeley, CA 94720, USA. ckerfeld@lbl.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113721" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/metabolism ; Canthaxanthin/*chemistry/metabolism ; Crystallography, X-Ray ; Models, Chemical ; *Photosynthesis ; Phycobilisomes/*chemistry ; Protein Structure, Secondary ; Protein Transport ; Synechocystis/*metabolism
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    Protein structure. Crystal structures of translocator protein (TSPO) and mutant mimic of a human polymorphism (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-01-31
    Description: The 18-kilodalton translocator protein (TSPO), proposed to be a key player in cholesterol transport into mitochondria, is highly expressed in steroidogenic tissues, metastatic cancer, and inflammatory and neurological diseases such as Alzheimer's and Parkinson's. TSPO ligands, including benzodiazepine drugs, are implicated in regulating apoptosis and are extensively used in diagnostic imaging. We report crystal structures (at 1.8, 2.4, and 2.5 angstrom resolution) of TSPO from Rhodobacter sphaeroides and a mutant that mimics the human Ala(147)--〉Thr(147) polymorphism associated with psychiatric disorders and reduced pregnenolone production. Crystals obtained in the lipidic cubic phase reveal the binding site of an endogenous porphyrin ligand and conformational effects of the mutation. The three crystal structures show the same tightly interacting dimer and provide insights into the controversial physiological role of TSPO and how the mutation affects cholesterol binding.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Fei -- Liu, Jian -- Zheng, Yi -- Garavito, R Michael -- Ferguson-Miller, Shelagh -- ACB-12002/PHS HHS/ -- AGM-12006/PHS HHS/ -- GM094625/GM/NIGMS NIH HHS/ -- GM26916/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 30;347(6221):555-8. doi: 10.1126/science.1260590.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. ; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. fergus20@msu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25635101" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Cholesterol/metabolism ; Crystallography, X-Ray ; Humans ; Hydrogen Bonding ; Isoquinolines/metabolism ; Ligands ; Membrane Transport Proteins/*chemistry/*metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry ; Polymorphism, Single Nucleotide ; Porphyrins/metabolism ; Protein Conformation ; Protein Multimerization ; Protein Structure, Secondary ; Protoporphyrins/metabolism ; Receptors, GABA/chemistry/genetics ; Rhodobacter sphaeroides/*chemistry
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    STRUCTURAL VIROLOGY. Conformational plasticity of a native retroviral capsid revealed by x-ray crystallography (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-06-06
    Description: Retroviruses depend on self-assembly of their capsid proteins (core particle) to yield infectious mature virions. Despite the essential role of the retroviral core, its high polymorphism has hindered high-resolution structural analyses. Here, we report the x-ray structure of the native capsid (CA) protein from bovine leukemia virus. CA is organized as hexamers that deviate substantially from sixfold symmetry, yet adjust to make two-dimensional pseudohexagonal arrays that mimic mature retroviral cores. Intra- and interhexameric quasi-equivalent contacts are uncovered, with flexible trimeric lateral contacts among hexamers, yet preserving very similar dimeric interfaces making the lattice. The conformation of each capsid subunit in the hexamer is therefore dictated by long-range interactions, revealing how the hexamers can also assemble into closed core particles, a relevant feature of retrovirus biology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Obal, G -- Trajtenberg, F -- Carrion, F -- Tome, L -- Larrieux, N -- Zhang, X -- Pritsch, O -- Buschiazzo, A -- New York, N.Y. -- Science. 2015 Jul 3;349(6243):95-8. doi: 10.1126/science.aaa5182. Epub 2015 Jun 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Pasteur de Montevideo, Unit of Protein Biophysics, Mataojo 2020, 11400, Montevideo, Uruguay. Departamento de Inmunobiologia, Facultad de Medicina, Universidad de la Republica, Avenida General Flores 2125, 11800, Montevideo, Uruguay. ; Institut Pasteur de Montevideo, Unit of Protein Crystallography, Mataojo 2020, 11400, Montevideo, Uruguay. ; Institut Pasteur de Montevideo, Unit of Protein Biophysics, Mataojo 2020, 11400, Montevideo, Uruguay. ; Institut Pasteur, Unite de Virologie Structurale, Departement de Virologie and CNRS Unite Mixte de Recherche 3569, 28, Rue du Docteur Roux, 75015, Paris, France. ; Institut Pasteur de Montevideo, Unit of Protein Biophysics, Mataojo 2020, 11400, Montevideo, Uruguay. Departamento de Inmunobiologia, Facultad de Medicina, Universidad de la Republica, Avenida General Flores 2125, 11800, Montevideo, Uruguay. pritsch@pasteur.edu.uy alebus@pasteur.edu.uy. ; Institut Pasteur de Montevideo, Unit of Protein Crystallography, Mataojo 2020, 11400, Montevideo, Uruguay. Institut Pasteur, Department of Structural Biology and Chemistry, 25, Rue du Dr Roux, 75015, Paris, France. pritsch@pasteur.edu.uy alebus@pasteur.edu.uy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26044299" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Capsid/*chemistry ; Capsid Proteins/*chemistry/genetics ; Cattle ; Crystallography, X-Ray ; Leukemia Virus, Bovine/*chemistry/genetics ; Molecular Sequence Data ; Mutation ; Protein Multimerization ; Protein Structure, Secondary
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    DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-01-13
    Description: XRCC4 and XLF are two structurally related proteins that function in DNA double-strand break (DSB) repair. Here, we identify human PAXX (PAralog of XRCC4 and XLF, also called C9orf142) as a new XRCC4 superfamily member and show that its crystal structure resembles that of XRCC4. PAXX interacts directly with the DSB-repair protein Ku and is recruited to DNA-damage sites in cells. Using RNA interference and CRISPR-Cas9 to generate PAXX(-/-) cells, we demonstrate that PAXX functions with XRCC4 and XLF to mediate DSB repair and cell survival in response to DSB-inducing agents. Finally, we reveal that PAXX promotes Ku-dependent DNA ligation in vitro and assembly of core nonhomologous end-joining (NHEJ) factors on damaged chromatin in cells. These findings identify PAXX as a new component of the NHEJ machinery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338599/" 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/PMC4338599/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ochi, Takashi -- Blackford, Andrew N -- Coates, Julia -- Jhujh, Satpal -- Mehmood, Shahid -- Tamura, Naoka -- Travers, Jon -- Wu, Qian -- Draviam, Viji M -- Robinson, Carol V -- Blundell, Tom L -- Jackson, Stephen P -- 11224/Cancer Research UK/United Kingdom -- 268536/European Research Council/International -- A11224/Cancer Research UK/United Kingdom -- C28598/A9787/Cancer Research UK/United Kingdom -- C6/A11224/Cancer Research UK/United Kingdom -- C6946/A14492/Cancer Research UK/United Kingdom -- WT092096/Wellcome Trust/United Kingdom -- WT093167/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2015 Jan 9;347(6218):185-8. doi: 10.1126/science.1261971.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. ; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK. ; Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, UK. ; Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK. ; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. s.jackson@gurdon.cam.ac.uk tlb20@cam.ac.uk. ; Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK. Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. s.jackson@gurdon.cam.ac.uk tlb20@cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25574025" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, Nuclear/*metabolism ; Cell Line, Tumor ; Crystallography, X-Ray ; *DNA Breaks, Double-Stranded ; *DNA End-Joining Repair ; DNA Repair Enzymes/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Humans ; Protein Structure, Secondary ; RNA Interference
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    A career is like a love affair (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-04-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jacobs, Madeleine -- New York, N.Y. -- Science. 2015 Apr 3;348(6230):150. doi: 10.1126/science.348.6230.150.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉A former editor-in-chief of C&EN, Madeleine Jacobs was CEO of ACS until she retired at the end of 2014. For more on life and careers, visit sciencecareers.sciencemag.org. Send your story to SciCareerEditor@aaas.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25838387" target="_blank"〉PubMed〈/a〉
    Keywords: *Career Choice ; Chemistry ; Female ; Humans ; *Journalism ; *Women, Working
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    Circadian rhythms. Atomic-scale origins of slowness in the cyanobacterial circadian clock (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-06-27
    Description: Circadian clocks generate slow and ordered cellular dynamics but consist of fast-moving bio-macromolecules; consequently, the origins of the overall slowness remain unclear. We identified the adenosine triphosphate (ATP) catalytic region [adenosine triphosphatase (ATPase)] in the amino-terminal half of the clock protein KaiC as the minimal pacemaker that controls the in vivo frequency of the cyanobacterial clock. Crystal structures of the ATPase revealed that the slowness of this ATPase arises from sequestration of a lytic water molecule in an unfavorable position and coupling of ATP hydrolysis to a peptide isomerization with high activation energy. The slow ATPase is coupled with another ATPase catalyzing autodephosphorylation in the carboxyl-terminal half of KaiC, yielding the circadian response frequency of intermolecular interactions with other clock-related proteins that influences the transcription and translation cycle.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abe, Jun -- Hiyama, Takuya B -- Mukaiyama, Atsushi -- Son, Seyoung -- Mori, Toshifumi -- Saito, Shinji -- Osako, Masato -- Wolanin, Julie -- Yamashita, Eiki -- Kondo, Takao -- Akiyama, Shuji -- New York, N.Y. -- Science. 2015 Jul 17;349(6245):312-6. doi: 10.1126/science.1261040. Epub 2015 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. ; Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. ; Division of Biological Science, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. ; Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. Department of Theoretical and Computational Molecular Science, Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. ; Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. Department of Theoretical and Computational Molecular Science, Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. ; Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. PSL Research University, Chimie ParisTech, 75005 Paris, France. ; Institute for Protein Research, Osaka University, 3-2 Yamada-oka, Suita 565-0871, Japan. ; Research Center of Integrative Molecular Systems (CIMoS), Institute for Molecular Science, 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. Department of Functional Molecular Science, SOKENDAI (The Graduate University for Advanced Studies), 38 Nishigo-Naka, Myodaiji, Okazaki 444-8585, Japan. akiyamas@ims.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113637" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*chemistry/genetics ; Adenosine Triphosphate/chemistry ; Bacterial Proteins/*chemistry/genetics ; Catalysis ; *Catalytic Domain ; Circadian Clocks/*physiology ; *Circadian Rhythm ; Circadian Rhythm Signaling Peptides and Proteins/*chemistry/genetics ; Crystallography, X-Ray ; Hydrolysis ; Synechococcus/enzymology/*physiology
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    Structure and inhibition of EV-D68, a virus that causes respiratory illness in children (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-01-03
    Description: Enterovirus D68 (EV-D68) is a member of Picornaviridae and is a causative agent of recent outbreaks of respiratory illness in children in the United States. We report here the crystal structures of EV-D68 and its complex with pleconaril, a capsid-binding compound that had been developed as an anti-rhinovirus drug. The hydrophobic drug-binding pocket in viral protein 1 contained density that is consistent with a fatty acid of about 10 carbon atoms. This density could be displaced by pleconaril. We also showed that pleconaril inhibits EV-D68 at a half-maximal effective concentration of 430 nanomolar and might, therefore, be a possible drug candidate to alleviate EV-D68 outbreaks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307789/" 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/PMC4307789/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Yue -- Sheng, Ju -- Fokine, Andrei -- Meng, Geng -- Shin, Woong-Hee -- Long, Feng -- Kuhn, Richard J -- Kihara, Daisuke -- Rossmann, Michael G -- AI11219/AI/NIAID NIH HHS/ -- R24 GM111072/GM/NIGMS NIH HHS/ -- R37 AI011219/AI/NIAID NIH HHS/ -- RR007707/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 2;347(6217):71-4. doi: 10.1126/science.1261962.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Hockmeyer Hall of Structural Biology, 240 South Martin Jischke Drive, Purdue University, West Lafayette, IN 47907, USA. ; Department of Biological Sciences, Hockmeyer Hall of Structural Biology, 240 South Martin Jischke Drive, Purdue University, West Lafayette, IN 47907, USA. Department of Computer Science, 305 North University Street, Purdue University, West Lafayette, IN 47907, USA. ; Department of Biological Sciences, Hockmeyer Hall of Structural Biology, 240 South Martin Jischke Drive, Purdue University, West Lafayette, IN 47907, USA. mr@purdue.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25554786" target="_blank"〉PubMed〈/a〉
    Keywords: Antiviral Agents/*chemistry/pharmacology/therapeutic use ; Capsid/*chemistry/drug effects/ultrastructure ; Child ; Crystallography, X-Ray ; Enterovirus D, Human/*chemistry/drug effects/ultrastructure ; Enterovirus Infections/drug therapy/epidemiology/*virology ; Humans ; Hydrophobic and Hydrophilic Interactions ; Oxadiazoles/*chemistry/pharmacology/therapeutic use ; Respiratory Tract Diseases/drug therapy/epidemiology/*virology ; United States/epidemiology ; Viral Proteins/chemistry/ultrastructure
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    Mitochondrial biology. Replication-transcription switch in human mitochondria (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-01-31
    Description: Coordinated replication and expression of the mitochondrial genome is critical for metabolically active cells during various stages of development. However, it is not known whether replication and transcription can occur simultaneously without interfering with each other and whether mitochondrial DNA copy number can be regulated by the transcription machinery. We found that interaction of human transcription elongation factor TEFM with mitochondrial RNA polymerase and nascent transcript prevents the generation of replication primers and increases transcription processivity and thereby serves as a molecular switch between replication and transcription, which appear to be mutually exclusive processes in mitochondria. TEFM may allow mitochondria to increase transcription rates and, as a consequence, respiration and adenosine triphosphate production without the need to replicate mitochondrial DNA, as has been observed during spermatogenesis and the early stages of embryogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677687/" 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/PMC4677687/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Agaronyan, Karen -- Morozov, Yaroslav I -- Anikin, Michael -- Temiakov, Dmitry -- R01 GM104231/GM/NIGMS NIH HHS/ -- R01GM104231/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 30;347(6221):548-51. doi: 10.1126/science.aaa0986.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, School of Osteopathic Medicine, Rowan University, 2 Medical Center Drive, Stratford, NJ 08084, USA. ; Department of Cell Biology, School of Osteopathic Medicine, Rowan University, 2 Medical Center Drive, Stratford, NJ 08084, USA. temiakdm@rowan.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25635099" target="_blank"〉PubMed〈/a〉
    Keywords: *DNA Replication ; DNA, Mitochondrial/*genetics/*metabolism ; DNA-Directed RNA Polymerases/chemistry/*metabolism ; G-Quadruplexes ; Genome, Mitochondrial ; Humans ; Mitochondria/genetics/metabolism ; Mitochondrial Proteins/chemistry/*metabolism ; Models, Genetic ; Models, Molecular ; RNA/chemistry/*metabolism ; Transcription Factors/*metabolism ; Transcription Termination, Genetic ; *Transcription, Genetic
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    Crystal structure of the metazoan Nup62*Nup58*Nup54 nucleoporin complex (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-08-22
    Description: Nuclear pore complexes (NPCs) conduct nucleocytoplasmic transport and gain transport selectivity through nucleoporin FG domains. Here, we report a structural analysis of the FG Nup62*58*54 complex, which is a crucial component of the transport system. It comprises a approximately 13 nanometer-long trimerization interface with an unusual 2W3F coil, a canonical heterotrimeric coiled coil, and a kink that enforces a compact six-helix bundle. Nup54 also contains a ferredoxin-like domain. We further identified a heterotrimeric Nup93-binding module for NPC anchorage. The quaternary structure alternations in the Nup62 complex, which were previously proposed to trigger a general gating of the NPC, are incompatible with the trimer structure. We suggest that the highly elongated Nup62 complex projects barrier-forming FG repeats far into the central NPC channel, supporting a barrier that guards the entire cross section.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chug, Hema -- Trakhanov, Sergei -- Hulsmann, Bastian B -- Pleiner, Tino -- Gorlich, Dirk -- New York, N.Y. -- Science. 2015 Oct 2;350(6256):106-10. doi: 10.1126/science.aac7420. Epub 2015 Aug 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Gottingen, Germany. ; Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Gottingen, Germany. goerlich@mpibpc.mpg.de.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26292704" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Crystallography, X-Ray ; Databases, Protein ; Nuclear Pore/chemistry/*ultrastructure ; Nuclear Pore Complex Proteins/chemistry/*ultrastructure ; Protein Structure, Tertiary ; Xenopus Proteins/chemistry/ultrastructure ; Xenopus laevis
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    Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-12-19
    Description: Voltage-gated sodium (Nav) channels propagate action potentials in excitable cells. Accordingly, Nav channels are therapeutic targets for many cardiovascular and neurological disorders. Selective inhibitors have been challenging to design because the nine mammalian Nav channel isoforms share high sequence identity and remain recalcitrant to high-resolution structural studies. Targeting the human Nav1.7 channel involved in pain perception, we present a protein-engineering strategy that has allowed us to determine crystal structures of a novel receptor site in complex with isoform-selective antagonists. GX-936 and related inhibitors bind to the activated state of voltage-sensor domain IV (VSD4), where their anionic aryl sulfonamide warhead engages the fourth arginine gating charge on the S4 helix. By opposing VSD4 deactivation, these compounds inhibit Nav1.7 through a voltage-sensor trapping mechanism, likely by stabilizing inactivated states of the channel. Residues from the S2 and S3 helices are key determinants of isoform selectivity, and bound phospholipids implicate the membrane as a modulator of channel function and pharmacology. Our results help to elucidate the molecular basis of voltage sensing and establish structural blueprints to design selective Nav channel antagonists.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ahuja, Shivani -- Mukund, Susmith -- Deng, Lunbin -- Khakh, Kuldip -- Chang, Elaine -- Ho, Hoangdung -- Shriver, Stephanie -- Young, Clint -- Lin, Sophia -- Johnson, J P Jr -- Wu, Ping -- Li, Jun -- Coons, Mary -- Tam, Christine -- Brillantes, Bobby -- Sampang, Honorio -- Mortara, Kyle -- Bowman, Krista K -- Clark, Kevin R -- Estevez, Alberto -- Xie, Zhiwei -- Verschoof, Henry -- Grimwood, Michael -- Dehnhardt, Christoph -- Andrez, Jean-Christophe -- Focken, Thilo -- Sutherlin, Daniel P -- Safina, Brian S -- Starovasnik, Melissa A -- Ortwine, Daniel F -- Franke, Yvonne -- Cohen, Charles J -- Hackos, David H -- Koth, Christopher M -- Payandeh, Jian -- New York, N.Y. -- Science. 2015 Dec 18;350(6267):aac5464. doi: 10.1126/science.aac5464.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Biology, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada. ; Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Chemistry, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada. ; Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. hackos.david@gene.com koth.christopher@gene.com payandeh.jian@gene.com. ; Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA. hackos.david@gene.com koth.christopher@gene.com payandeh.jian@gene.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26680203" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cell Membrane/chemistry ; Crystallization/methods ; Crystallography, X-Ray ; DNA Mutational Analysis ; Humans ; Models, Molecular ; Molecular Sequence Data ; NAV1.7 Voltage-Gated Sodium Channel/*chemistry/genetics ; Pain Perception/drug effects ; Protein Engineering ; Protein Isoforms/antagonists & inhibitors/chemistry ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Sodium Channel Blockers/*chemistry/*pharmacology ; Sulfonamides/*chemistry/*pharmacology ; Thiadiazoles/*chemistry/*pharmacology
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    Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-10-17
    Description: Telomerase helps maintain telomeres by processive synthesis of telomere repeat DNA at their 3'-ends, using an integral telomerase RNA (TER) and telomerase reverse transcriptase (TERT). We report the cryo-electron microscopy structure of Tetrahymena telomerase at ~9 angstrom resolution. In addition to seven known holoenzyme proteins, we identify two additional proteins that form a complex (TEB) with single-stranded telomere DNA-binding protein Teb1, paralogous to heterotrimeric replication protein A (RPA). The p75-p45-p19 subcomplex is identified as another RPA-related complex, CST (CTC1-STN1-TEN1). This study reveals the paths of TER in the TERT-TER-p65 catalytic core and single-stranded DNA exit; extensive subunit interactions of the TERT essential N-terminal domain, p50, and TEB; and other subunit identities and structures, including p19 and p45C crystal structures. Our findings provide structural and mechanistic insights into telomerase holoenzyme function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687456/" 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/PMC4687456/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Jiansen -- Chan, Henry -- Cash, Darian D -- Miracco, Edward J -- Ogorzalek Loo, Rachel R -- Upton, Heather E -- Cascio, Duilio -- O'Brien Johnson, Reid -- Collins, Kathleen -- Loo, Joseph A -- Zhou, Z Hong -- Feigon, Juli -- GM007185/GM/NIGMS NIH HHS/ -- GM048123/GM/NIGMS NIH HHS/ -- GM071940/GM/NIGMS NIH HHS/ -- GM101874/GM/NIGMS NIH HHS/ -- GM103479/GM/NIGMS NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- P41 RR015301/RR/NCRR NIH HHS/ -- R01 GM048123/GM/NIGMS NIH HHS/ -- R01 GM054198/GM/NIGMS NIH HHS/ -- R01 GM071940/GM/NIGMS NIH HHS/ -- R01 GM103479/GM/NIGMS NIH HHS/ -- R01GM054198/GM/NIGMS NIH HHS/ -- S10OD018111/OD/NIH HHS/ -- S10RR23057/RR/NCRR NIH HHS/ -- UL1TR000124/TR/NCATS NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 30;350(6260):aab4070. doi: 10.1126/science.aab4070. Epub 2015 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA. California Nanosystems Institute, UCLA, Los Angeles, CA 90095, USA. ; Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. ; Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA. ; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA. ; Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. UCLA-U.S. Department of Energy (DOE) Institute of Genomics and Proteomics, UCLA, Los Angeles, CA 90095, USA. ; Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. Department of Biological Chemistry, UCLA, Los Angeles, CA 90095, USA. UCLA-U.S. Department of Energy (DOE) Institute of Genomics and Proteomics, UCLA, Los Angeles, CA 90095, USA. ; Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA 90095, USA. California Nanosystems Institute, UCLA, Los Angeles, CA 90095, USA. ; Department of Chemistry and Biochemistry, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA. California Nanosystems Institute, UCLA, Los Angeles, CA 90095, USA. UCLA-U.S. Department of Energy (DOE) Institute of Genomics and Proteomics, UCLA, Los Angeles, CA 90095, USA. feigon@mbi.ucla.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472759" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Cryoelectron Microscopy ; Crystallography, X-Ray ; DNA, Single-Stranded/chemistry ; Holoenzymes/chemistry ; Protein Binding ; Protein Conformation ; Protein Subunits/chemistry ; RNA/*chemistry ; Replication Protein A/chemistry ; Telomerase/*chemistry ; Telomere/chemistry ; Telomere Homeostasis ; Telomere-Binding Proteins ; Tetrahymena/*enzymology
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    STRUCTURAL BIOLOGY. A Cas9-guide RNA complex preorganized for target DNA recognition (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-06-27
    Description: Bacterial adaptive immunity uses CRISPR (clustered regularly interspaced short palindromic repeats)-associated (Cas) proteins together with CRISPR transcripts for foreign DNA degradation. In type II CRISPR-Cas systems, activation of Cas9 endonuclease for DNA recognition upon guide RNA binding occurs by an unknown mechanism. Crystal structures of Cas9 bound to single-guide RNA reveal a conformation distinct from both the apo and DNA-bound states, in which the 10-nucleotide RNA "seed" sequence required for initial DNA interrogation is preordered in an A-form conformation. This segment of the guide RNA is essential for Cas9 to form a DNA recognition-competent structure that is poised to engage double-stranded DNA target sequences. We construe this as convergent evolution of a "seed" mechanism reminiscent of that used by Argonaute proteins during RNA interference in eukaryotes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Fuguo -- Zhou, Kaihong -- Ma, Linlin -- Gressel, Saskia -- Doudna, Jennifer A -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jun 26;348(6242):1477-81. doi: 10.1126/science.aab1452.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. ; Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA. ; Max Planck Institute for Biophysical Chemistry, 37077 Gottingen, Germany. ; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA. California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720, USA. Department of Chemistry, University of California, Berkeley, CA 94720, USA. Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Innovative Genomics Initiative, University of California, Berkeley, CA 94720, USA. doudna@berkeley.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113724" target="_blank"〉PubMed〈/a〉
    Keywords: Argonaute Proteins/*chemistry ; Base Sequence ; *CRISPR-Cas Systems ; Caspase 9/*chemistry/genetics ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Crystallography, X-Ray ; DNA/chemistry ; *DNA Cleavage ; Enzyme Activation ; Evolution, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Protein Structure, Tertiary ; RNA Interference ; RNA, Guide/*chemistry ; Streptococcus pyogenes/*enzymology
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  • 88
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    Structural basis of histone H3K27 trimethylation by an active polycomb repressive complex 2 (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-10-17
    Description: Polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 trimethylation (H3K27me3), a hallmark of gene silencing. Here we report the crystal structures of an active PRC2 complex of 170 kilodaltons from the yeast Chaetomium thermophilum in both basal and stimulated states, which contain Ezh2, Eed, and the VEFS domain of Suz12 and are bound to a cancer-associated inhibiting H3K27M peptide and a S-adenosyl-l-homocysteine cofactor. The stimulated complex also contains an additional stimulating H3K27me3 peptide. Eed is engulfed by a belt-like structure of Ezh2, and Suz12(VEFS) contacts both of these two subunits to confer an unusual split active SET domain for catalysis. Comparison of PRC2 in the basal and stimulated states reveals a mobile Ezh2 motif that responds to stimulation to allosterically regulate the active site.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiao, Lianying -- Liu, Xin -- GM114576/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 16;350(6258):aac4383. doi: 10.1126/science.aac4383. Epub 2015 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Research, Department of Obstetrics and Gynecology and Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ; Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Research, Department of Obstetrics and Gynecology and Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. xin.liu@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472914" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Sequence ; Catalysis ; Catalytic Domain ; Chaetomium/genetics/*metabolism ; Crystallography, X-Ray ; Fungal Proteins/antagonists & inhibitors/*chemistry/metabolism ; *Gene Silencing ; Histones/*metabolism ; Humans ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Methylation ; Molecular Sequence Data ; Mutation ; Neoplasms/genetics ; Polycomb Repressive Complex 2/antagonists & inhibitors/*chemistry/metabolism ; Protein Structure, Tertiary ; S-Adenosylhomocysteine/chemistry/metabolism ; Transcription, Genetic
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    Transition states. Trapping a transition state in a computationally designed protein bottle (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-02-24
    Description: The fleeting lifetimes of the transition states (TSs) of chemical reactions make determination of their three-dimensional structures by diffraction methods a challenge. Here, we used packing interactions within the core of a protein to stabilize the planar TS conformation for rotation around the central carbon-carbon bond of biphenyl so that it could be directly observed by x-ray crystallography. The computational protein design software Rosetta was used to design a pocket within threonyl-transfer RNA synthetase from the thermophile Pyrococcus abyssi that forms complementary van der Waals interactions with a planar biphenyl. This latter moiety was introduced biosynthetically as the side chain of the noncanonical amino acid p-biphenylalanine. Through iterative rounds of computational design and structural analysis, we identified a protein in which the side chain of p-biphenylalanine is trapped in the energetically disfavored, coplanar conformation of the TS of the bond rotation reaction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581533/" 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/PMC4581533/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pearson, Aaron D -- Mills, Jeremy H -- Song, Yifan -- Nasertorabi, Fariborz -- Han, Gye Won -- Baker, David -- Stevens, Raymond C -- Schultz, Peter G -- 2 R01 GM097206-05/GM/NIGMS NIH HHS/ -- F32 GM099210/GM/NIGMS NIH HHS/ -- F32GM099210/GM/NIGMS NIH HHS/ -- R01 GM097206/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):863-7. doi: 10.1126/science.aaa2424.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. ; Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA. ; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. Howard Hughes Medical Institute (HHMI), University of Washington, Seattle, WA 98195, USA. ; Department of Chemistry and Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. schultz@scripps.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700516" target="_blank"〉PubMed〈/a〉
    Keywords: Alanine/*analogs & derivatives/chemistry ; Archaeal Proteins/*chemistry ; Biphenyl Compounds/*chemistry ; Computer Simulation ; Computer-Aided Design ; Crystallography, X-Ray ; Entropy ; Models, Chemical ; Protein Structure, Secondary ; Pyrococcus abyssi/*enzymology ; Software ; Threonine-tRNA Ligase/*chemistry
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    Structural biology. Structural basis for Notch1 engagement of Delta-like 4 (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-02-24
    Description: Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL). The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1-DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation. Notch1 epidermal growth factor-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag-2 (DSL) domain and module at the N-terminus of Notch ligands (MNNL) domains, respectively. Threonine and serine residues on Notch1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445638/" 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/PMC4445638/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Luca, Vincent C -- Jude, Kevin M -- Pierce, Nathan W -- Nachury, Maxence V -- Fischer, Suzanne -- Garcia, K Christopher -- 1R01-GM097015/GM/NIGMS NIH HHS/ -- R01 GM097015/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):847-53. doi: 10.1126/science.1261093.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. kcgarcia@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700513" target="_blank"〉PubMed〈/a〉
    Keywords: Alagille Syndrome/genetics ; Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Cell Line ; Conserved Sequence ; Crystallography, X-Ray ; Fucose/chemistry ; Glucose/chemistry ; Glycosylation ; Intracellular Signaling Peptides and Proteins/*chemistry/genetics ; Ligands ; Membrane Proteins/*chemistry/genetics/ultrastructure ; Molecular Sequence Data ; Molecular Targeted Therapy ; Polysaccharides/chemistry ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics ; Protein Binding ; Protein Structure, Tertiary ; Rats ; Receptor, Notch1/*chemistry/genetics/ultrastructure ; Serine/chemistry/genetics ; Threonine/chemistry/genetics
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    Ribosome. The structure of the human mitochondrial ribosome (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-04-04
    Description: The highly divergent ribosomes of human mitochondria (mitoribosomes) synthesize 13 essential proteins of oxidative phosphorylation complexes. We have determined the structure of the intact mitoribosome to 3.5 angstrom resolution by means of single-particle electron cryogenic microscopy. It reveals 80 extensively interconnected proteins, 36 of which are specific to mitochondria, and three ribosomal RNA molecules. The head domain of the small subunit, particularly the messenger (mRNA) channel, is highly remodeled. Many intersubunit bridges are specific to the mitoribosome, which adopts conformations involving ratcheting or rolling of the small subunit that are distinct from those seen in bacteria or eukaryotes. An intrinsic guanosine triphosphatase mediates a contact between the head and central protuberance. The structure provides a reference for analysis of mutations that cause severe pathologies and for future drug design.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501431/" 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/PMC4501431/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Amunts, Alexey -- Brown, Alan -- Toots, Jaan -- Scheres, Sjors H W -- Ramakrishnan, V -- 096570/Wellcome Trust/United Kingdom -- MC_U105184332/Medical Research Council/United Kingdom -- MC_UP_A025_1013/Medical Research Council/United Kingdom -- WT096570/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2015 Apr 3;348(6230):95-8. doi: 10.1126/science.aaa1193. Epub 2015 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council (MRC) Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. ; Medical Research Council (MRC) Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. ramak@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25838379" target="_blank"〉PubMed〈/a〉
    Keywords: Aminoglycosides/pharmacology/therapeutic use ; Anti-Bacterial Agents/pharmacology ; Crystallography, X-Ray ; Drug Resistance, Bacterial/genetics ; GTP Phosphohydrolases/chemistry ; Genetic Diseases, Inborn/drug therapy/genetics ; Humans ; Mitochondria/chemistry/*ultrastructure ; RNA, Messenger/chemistry ; RNA, Ribosomal/chemistry ; Ribosomal Proteins/chemistry ; Ribosomes/chemistry/genetics/*ultrastructure
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    DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-05-23
    Description: The development of effective pharmacological inhibitors of multidomain scaffold proteins, notably transcription factors, is a particularly challenging problem. In part, this is because many small-molecule antagonists disrupt the activity of only one domain in the target protein. We devised a chemical strategy that promotes ligand-dependent target protein degradation using as an example the transcriptional coactivator BRD4, a protein critical for cancer cell growth and survival. We appended a competitive antagonist of BET bromodomains to a phthalimide moiety to hijack the cereblon E3 ubiquitin ligase complex. The resultant compound, dBET1, induced highly selective cereblon-dependent BET protein degradation in vitro and in vivo and delayed leukemia progression in mice. A second series of probes resulted in selective degradation of the cytosolic protein FKBP12. This chemical strategy for controlling target protein stability may have implications for therapeutically targeting previously intractable proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winter, Georg E -- Buckley, Dennis L -- Paulk, Joshiawa -- Roberts, Justin M -- Souza, Amanda -- Dhe-Paganon, Sirano -- Bradner, James E -- P01 CA066996/CA/NCI NIH HHS/ -- P01-CA066996/CA/NCI NIH HHS/ -- R01-CA176745/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 19;348(6241):1376-81. doi: 10.1126/science.aab1433. Epub 2015 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. ; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. james_bradner@dfci.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25999370" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Azepines/chemistry/*pharmacology/therapeutic use ; Cell Line, Tumor ; Crystallography, X-Ray ; Disease Models, Animal ; *Drug Design ; Leukemia, Promyelocytic, Acute/drug therapy ; Ligands ; Mice ; Molecular Targeted Therapy ; Nuclear Proteins/antagonists & inhibitors/chemistry/*metabolism ; Peptide Hydrolases/*metabolism ; Phthalimides/*chemistry ; Protein Stability/drug effects ; Protein Structure, Tertiary ; Proteolysis/*drug effects ; Tacrolimus Binding Protein 1A/metabolism ; Thalidomide/*analogs & derivatives/chemistry/pharmacology/therapeutic use ; Transcription Factors/antagonists & inhibitors/chemistry/*metabolism ; Ubiquitin-Protein Ligases/metabolism
    Print ISSN: 0036-8075
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    Viral replication. Structural basis for RNA replication by the hepatitis C virus polymerase (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-02-14
    Description: Nucleotide analog inhibitors have shown clinical success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA replication by determining crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis. Our analysis revealed that highly conserved active-site residues in NS5B position the primer for in-line attack on the incoming nucleotide. A beta loop and a C-terminal membrane-anchoring linker occlude the active-site cavity in the apo state, retract in the primed initiation assembly to enforce replication of the HCV genome from the 3' terminus, and vacate the active-site cavity during elongation. We investigated the incorporation of nucleotide analog inhibitors, including the clinically active metabolite formed by sofosbuvir, to elucidate key molecular interactions in the active site.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Appleby, Todd C -- Perry, Jason K -- Murakami, Eisuke -- Barauskas, Ona -- Feng, Joy -- Cho, Aesop -- Fox, David 3rd -- Wetmore, Diana R -- McGrath, Mary E -- Ray, Adrian S -- Sofia, Michael J -- Swaminathan, S -- Edwards, Thomas E -- New York, N.Y. -- Science. 2015 Feb 13;347(6223):771-5. doi: 10.1126/science.1259210.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. todd.appleby@gilead.com tedwards@be4.com. ; Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. ; Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA. ; Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA. todd.appleby@gilead.com tedwards@be4.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25678663" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; Hepacivirus/enzymology/genetics/*physiology ; Molecular Sequence Data ; Protein Structure, Secondary ; RNA Replicase/*chemistry ; RNA, Viral/*biosynthesis ; Ribonucleotides/*chemistry ; Sofosbuvir ; Uridine Monophosphate/analogs & derivatives/chemistry ; Viral Nonstructural Proteins/*chemistry ; *Virus Replication
    Print ISSN: 0036-8075
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    Crystal structure of the anion exchanger domain of human erythrocyte band 3 (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-11-07
    Description: Anion exchanger 1 (AE1), also known as band 3 or SLC4A1, plays a key role in the removal of carbon dioxide from tissues by facilitating the exchange of chloride and bicarbonate across the plasma membrane of erythrocytes. An isoform of AE1 is also present in the kidney. Specific mutations in human AE1 cause several types of hereditary hemolytic anemias and/or distal renal tubular acidosis. Here we report the crystal structure of the band 3 anion exchanger domain (AE1(CTD)) at 3.5 angstroms. The structure is locked in an outward-facing open conformation by an inhibitor. Comparing this structure with a substrate-bound structure of the uracil transporter UraA in an inward-facing conformation allowed us to identify the anion-binding position in the AE1(CTD), and to propose a possible transport mechanism that could explain why selected mutations lead to disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arakawa, Takatoshi -- Kobayashi-Yurugi, Takami -- Alguel, Yilmaz -- Iwanari, Hiroko -- Hatae, Hinako -- Iwata, Momi -- Abe, Yoshito -- Hino, Tomoya -- Ikeda-Suno, Chiyo -- Kuma, Hiroyuki -- Kang, Dongchon -- Murata, Takeshi -- Hamakubo, Takao -- Cameron, Alexander D -- Kobayashi, Takuya -- Hamasaki, Naotaka -- Iwata, So -- BB/D019516/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- WT089809/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):680-4. doi: 10.1126/science.aaa4335.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. JST, Research Acceleration Program, Membrane Protein Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. ; Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. Research Complex at Harwell Rutherford, Appleton Laboratory, Harwell Oxford, Didcot, Oxfordshire OX11 0FA, UK. ; Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan. ; Faculty of Pharmaceutical Sciences, Nagasaki International University, 2825-7 Huis Ten Bosch-cho, Sasebo, Nagasaki 859-3298, Japan. ; Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. ; Department of Protein Structure, Function and Design, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. ; Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage, Chiba 263-8522, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. Research Complex at Harwell Rutherford, Appleton Laboratory, Harwell Oxford, Didcot, Oxfordshire OX11 0FA, UK. School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. JST, Research Acceleration Program, Membrane Protein Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Platform for Drug Discovery, Informatics, and Structural Life Science, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. JST, Research Acceleration Program, Membrane Protein Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. Research Complex at Harwell Rutherford, Appleton Laboratory, Harwell Oxford, Didcot, Oxfordshire OX11 0FA, UK. Platform for Drug Discovery, Informatics, and Structural Life Science, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542571" target="_blank"〉PubMed〈/a〉
    Keywords: Anion Exchange Protein 1, Erythrocyte/*chemistry/genetics ; Crystallography, X-Ray ; Disease/genetics ; Escherichia coli Proteins/chemistry ; Humans ; Membrane Transport Proteins/chemistry ; Mutation ; Protein Structure, Secondary ; Protein Structure, Tertiary
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    Protein structure. Engineering of a superhelicase through conformational control (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-04-18
    Description: Conformational control of biomolecular activities can reveal functional insights and enable the engineering of novel activities. Here we show that conformational control through intramolecular cross-linking of a helicase monomer with undetectable unwinding activity converts it into a superhelicase that can unwind thousands of base pairs processively, even against a large opposing force. A natural partner that enhances the helicase activity is shown to achieve its stimulating role also by selectively stabilizing the active conformation. Our work provides insight into the regulation of nucleic acid unwinding activity and introduces a monomeric superhelicase without nuclease activities, which may be useful for biotechnological applications.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417355/" 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/PMC4417355/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arslan, Sinan -- Khafizov, Rustem -- Thomas, Christopher D -- Chemla, Yann R -- Ha, Taekjip -- GM065367/GM/NIGMS NIH HHS/ -- R01 GM065367/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Apr 17;348(6232):344-7. doi: 10.1126/science.aaa0445.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Physics Department and Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. ; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK. ; Physics Department and Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Howard Hughes Medical Institute, University of Illinois, Urbana, IL 61801, USA. tjha@illinois.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25883358" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/genetics ; Cross-Linking Reagents/chemistry ; Crystallography, X-Ray ; DNA Helicases/*chemistry/genetics ; *DNA Replication ; DNA, Single-Stranded/*chemistry ; Deoxyribonucleases/chemistry/genetics ; Enzyme Stability ; Escherichia coli Proteins/*chemistry/genetics ; Protein Conformation ; Protein Engineering
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  • 96
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    TRANSCRIPTION. Allosteric transcriptional regulation via changes in the overall topology of the core promoter (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-08-22
    Description: Many transcriptional activators act at a distance from core promoter elements and work by recruiting RNA polymerase through protein-protein interactions. We show here how the prokaryotic regulatory protein CueR both represses and activates transcription by differentially modulating local DNA structure within the promoter. Structural studies reveal that the repressor state slightly bends the promoter DNA, precluding optimal RNA polymerase-promoter recognition. Upon binding a metal ion in the allosteric site, CueR switches into an activator conformation. It maintains all protein-DNA contacts but introduces torsional stresses that kink and undertwist the promoter, stabilizing an A-form DNA-like conformation. These factors switch on and off transcription by exerting dynamic control of DNA stereochemistry, reshaping the core promoter and making it a better or worse substrate for polymerase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617686/" 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/PMC4617686/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Philips, Steven J -- Canalizo-Hernandez, Monica -- Yildirim, Ilyas -- Schatz, George C -- Mondragon, Alfonso -- O'Halloran, Thomas V -- R01 GM038784/GM/NIGMS NIH HHS/ -- R01GM038784/GM/NIGMS NIH HHS/ -- U54 CA143869/CA/NCI NIH HHS/ -- U54 CA193419/CA/NCI NIH HHS/ -- U54CA143869/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 21;349(6250):877-81. doi: 10.1126/science.aaa9809.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA. ; Department of Chemistry, Northwestern University, Evanston, IL 60208, USA. ; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA. t-ohalloran@northwestern.edu a-mondragon@northwestern.edu. ; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA. Department of Chemistry, Northwestern University, Evanston, IL 60208, USA. The Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA. t-ohalloran@northwestern.edu a-mondragon@northwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26293965" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Allosteric Site ; Bacterial Proteins/chemistry/*metabolism ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; DNA-Binding Proteins/chemistry/*metabolism ; DNA-Directed RNA Polymerases/metabolism ; Nucleic Acid Conformation ; Promoter Regions, Genetic/*genetics ; Protein Multimerization ; Protein Structure, Secondary ; *Transcription, Genetic ; *Transcriptional Activation
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    A direct role for the Sec1/Munc18-family protein Vps33 as a template for SNARE assembly (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-09-05
    Description: Fusion of intracellular transport vesicles requires soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and Sec1/Munc18-family (SM) proteins. Membrane-bridging SNARE complexes are critical for fusion, but their spontaneous assembly is inefficient and may require SM proteins in vivo. We report x-ray structures of Vps33, the SM subunit of the yeast homotypic fusion and vacuole protein-sorting (HOPS) complex, bound to two individual SNAREs. The two SNAREs, one from each membrane, are held in the correct orientation and register for subsequent complex assembly. Vps33 and potentially other SM proteins could thus act as templates for generating partially zipped SNARE assembly intermediates. HOPS was essential to mediate SNARE complex assembly at physiological SNARE concentrations. Thus, Vps33 appears to catalyze SNARE complex assembly through specific SNARE motif recognition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727825/" 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/PMC4727825/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baker, Richard W -- Jeffrey, Philip D -- Zick, Michael -- Phillips, Ben P -- Wickner, William T -- Hughson, Frederick M -- GM071574/GM/NIGMS NIH HHS/ -- GM23377/GM/NIGMS NIH HHS/ -- R01 GM071574/GM/NIGMS NIH HHS/ -- T32 GM007388/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Sep 4;349(6252):1111-4. doi: 10.1126/science.aac7906.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. ; Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. hughson@princeton.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26339030" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Membrane Proteins/chemistry/metabolism ; Munc18 Proteins/*metabolism ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Qa-SNARE Proteins/*metabolism ; R-SNARE Proteins/*metabolism ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism/ultrastructure ; Synaptosomal-Associated Protein 25/chemistry/metabolism ; Vesicular Transport Proteins/chemistry/*metabolism/ultrastructure
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    Structure of a yeast spliceosome at 3.6-angstrom resolution (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-08-22
    Description: Splicing of precursor messenger RNA (pre-mRNA) in yeast is executed by the spliceosome, which consists of five small nuclear ribonucleoproteins (snRNPs), NTC (nineteen complex), NTC-related proteins (NTR), and a number of associated enzymes and cofactors. Here, we report the three-dimensional structure of a Schizosaccharomyces pombe spliceosome at 3.6-angstrom resolution, revealed by means of single-particle cryogenic electron microscopy. This spliceosome contains U2 and U5 snRNPs, NTC, NTR, U6 small nuclear RNA, and an RNA intron lariat. The atomic model includes 10,574 amino acids from 37 proteins and four RNA molecules, with a combined molecular mass of approximately 1.3 megadaltons. Spp42 (Prp8 in Saccharomyces cerevisiae), the key protein component of the U5 snRNP, forms a central scaffold and anchors the catalytic center. Both the morphology and the placement of protein components appear to have evolved to facilitate the dynamic process of pre-mRNA splicing. Our near-atomic-resolution structure of a central spliceosome provides a molecular framework for mechanistic understanding of pre-mRNA splicing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yan, Chuangye -- Hang, Jing -- Wan, Ruixue -- Huang, Min -- Wong, Catherine C L -- Shi, Yigong -- New York, N.Y. -- Science. 2015 Sep 11;349(6253):1182-91. doi: 10.1126/science.aac7629. Epub 2015 Aug 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26292707" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Cryoelectron Microscopy ; Models, Molecular ; Protein Structure, Secondary ; RNA, Small Nuclear/chemistry ; Repressor Proteins/chemistry ; Ribonucleoprotein, U5 Small Nuclear/chemistry ; Schizosaccharomyces/*ultrastructure ; Schizosaccharomyces pombe Proteins/chemistry ; Spliceosomes/*chemistry/*ultrastructure
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  • 99
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    Protein targeting. Structure of the Get3 targeting factor in complex with its membrane protein cargo (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-03-07
    Description: Tail-anchored (TA) proteins are a physiologically important class of membrane proteins targeted to the endoplasmic reticulum by the conserved guided-entry of TA proteins (GET) pathway. During transit, their hydrophobic transmembrane domains (TMDs) are chaperoned by the cytosolic targeting factor Get3, but the molecular nature of the functional Get3-TA protein targeting complex remains unknown. We reconstituted the physiologic assembly pathway for a functional targeting complex and showed that it comprises a TA protein bound to a Get3 homodimer. Crystal structures of Get3 bound to different TA proteins showed an alpha-helical TMD occupying a hydrophobic groove that spans the Get3 homodimer. Our data elucidate the mechanism of TA protein recognition and shielding by Get3 and suggest general principles of hydrophobic domain chaperoning by cellular targeting factors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413028/" 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/PMC4413028/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mateja, Agnieszka -- Paduch, Marcin -- Chang, Hsin-Yang -- Szydlowska, Anna -- Kossiakoff, Anthony A -- Hegde, Ramanujan S -- Keenan, Robert J -- MC_UP_A022_1007/Medical Research Council/United Kingdom -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 GM086487/GM/NIGMS NIH HHS/ -- U01 GM094588/GM/NIGMS NIH HHS/ -- U54 GM087519/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Mar 6;347(6226):1152-5. doi: 10.1126/science.1261671.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. ; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. rhegde@mrc-lmb.cam.ac.uk bkeenan@uchicago.edu. ; Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. rhegde@mrc-lmb.cam.ac.uk bkeenan@uchicago.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25745174" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*chemistry/metabolism ; Crystallography, X-Ray ; Cytosol/enzymology ; Guanine Nucleotide Exchange Factors/*chemistry/metabolism ; Hydrophobic and Hydrophilic Interactions ; Membrane Proteins/*chemistry/metabolism ; Molecular Chaperones/chemistry/metabolism ; Multiprotein Complexes/chemistry/metabolism ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Transport ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism
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  • 100
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    TRANSCRIPTION. Structures of the RNA polymerase-sigma54 reveal new and conserved regulatory strategies (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-08-22
    Description: Transcription by RNA polymerase (RNAP) in bacteria requires specific promoter recognition by sigma factors. The major variant sigma factor (sigma(54)) initially forms a transcriptionally silent complex requiring specialized adenosine triphosphate-dependent activators for initiation. Our crystal structure of the 450-kilodalton RNAP-sigma(54) holoenzyme at 3.8 angstroms reveals molecular details of sigma(54) and its interactions with RNAP. The structure explains how sigma(54) targets different regions in RNAP to exert its inhibitory function. Although sigma(54) and the major sigma factor, sigma(70), have similar functional domains and contact similar regions of RNAP, unanticipated differences are observed in their domain arrangement and interactions with RNAP, explaining their distinct properties. Furthermore, we observe evolutionarily conserved regulatory hotspots in RNAPs that can be targeted by a diverse range of mechanisms to fine tune transcription.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681505/" 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/PMC4681505/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Yun -- Darbari, Vidya C -- Zhang, Nan -- Lu, Duo -- Glyde, Robert -- Wang, Yi-Ping -- Winkelman, Jared T -- Gourse, Richard L -- Murakami, Katsuhiko S -- Buck, Martin -- Zhang, Xiaodong -- 098412/Wellcome Trust/United Kingdom -- BB/C504700/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- GM087350/GM/NIGMS NIH HHS/ -- R01 GM087350/GM/NIGMS NIH HHS/ -- R37 GM37048/GM/NIGMS NIH HHS/ -- Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Aug 21;349(6250):882-5. doi: 10.1126/science.aab1478.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Structural Biology, Imperial College London, South Kensington SW7 2AZ, UK. State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, China. ; Centre for Structural Biology, Imperial College London, South Kensington SW7 2AZ, UK. Department of Medicine, Imperial College London, South Kensington SW7 2AZ, UK. ; Department of Life Sciences, Imperial College London, South Kensington SW7 2AZ, UK. ; Centre for Structural Biology, Imperial College London, South Kensington SW7 2AZ, UK. ; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, China. ; Department of Bacteriology, University of Wisconsin, Madison, WI 53706, USA. ; Department of Biochemistry and Molecular Biology, Center for RNA Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA. ; Centre for Structural Biology, Imperial College London, South Kensington SW7 2AZ, UK. Department of Medicine, Imperial College London, South Kensington SW7 2AZ, UK. xiaodong.zhang@imperial.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26293966" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Enzyme Stability ; *Evolution, Molecular ; *Gene Expression Regulation ; Holoenzymes/chemistry ; Protein Conformation ; Protein Structure, Tertiary ; RNA Polymerase Sigma 54/*chemistry/genetics ; *Transcription, Genetic
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