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  • Crystallography, X-Ray  (65)
  • Nature Publishing Group (NPG)  (65)
  • American Institute of Physics (AIP)
  • Cell Press
  • Wiley-Blackwell
  • 2010-2014  (65)
  • 1985-1989
  • 2012  (65)
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  • 2010-2014  (65)
  • 1985-1989
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  • 1
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    Visualizing molecular juggling within a B12-dependent methyltransferase complex (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-16
    Description: Derivatives of vitamin B(12) are used in methyl group transfer in biological processes as diverse as methionine synthesis in humans and CO(2) fixation in acetogenic bacteria. This seemingly straightforward reaction requires large, multimodular enzyme complexes that adopt multiple conformations to alternately activate, protect and perform catalysis on the reactive B(12) cofactor. Crystal structures determined thus far have provided structural information for only fragments of these complexes, inspiring speculation about the overall protein assembly and conformational movements inherent to activity. Here we present X-ray crystal structures of a complete 220 kDa complex that contains all enzymes responsible for B(12)-dependent methyl transfer, namely the corrinoid iron-sulphur protein and its methyltransferase from the model acetogen Moorella thermoacetica. These structures provide the first three-dimensional depiction of all protein modules required for the activation, protection and catalytic steps of B(12)-dependent methyl transfer. In addition, the structures capture B(12) at multiple locations between its 'resting' and catalytic positions, allowing visualization of the dramatic protein rearrangements that enable methyl transfer and identification of the trajectory for B(12) movement within the large enzyme scaffold. The structures are also presented alongside in crystallo spectroscopic data, which confirm enzymatic activity within crystals and demonstrate the largest known conformational movements of proteins in a crystalline state. Taken together, this work provides a model for the molecular juggling that accompanies turnover and helps explain why such an elaborate protein framework is required for such a simple, yet biologically essential reaction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326194/" 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/PMC3326194/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kung, Yan -- Ando, Nozomi -- Doukov, Tzanko I -- Blasiak, Leah C -- Bender, Gunes -- Seravalli, Javier -- Ragsdale, Stephen W -- Drennan, Catherine L -- GM39451/GM/NIGMS NIH HHS/ -- GM69857/GM/NIGMS NIH HHS/ -- R01 GM039451/GM/NIGMS NIH HHS/ -- R01 GM039451-25/GM/NIGMS NIH HHS/ -- R01 GM069857/GM/NIGMS NIH HHS/ -- R37 GM039451/GM/NIGMS NIH HHS/ -- RR-15301/RR/NCRR NIH HHS/ -- T32 GM008334/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 14;484(7393):265-9. doi: 10.1038/nature10916.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22419154" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Biocatalysis ; Corrinoids/metabolism ; Crystallography, X-Ray ; Folic Acid/metabolism ; Iron-Sulfur Proteins/*chemistry/*metabolism ; Methylation ; Methyltransferases/*chemistry/*metabolism ; Models, Biological ; Models, Molecular ; Moorella/chemistry/*enzymology ; Protein Multimerization ; Protein Structure, Tertiary ; Vitamin B 12/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Structural plasticity and dynamic selectivity of acid-sensing ion channel-spider toxin complexes (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-07-31
    Description: Acid-sensing ion channels (ASICs) are voltage-independent, amiloride-sensitive channels involved in diverse physiological processes ranging from nociception to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of channel activation. Here we show that psalmotoxin activates non-selective and Na(+)-selective currents in chicken ASIC1a at pH 7.25 and 5.5, respectively. Crystal structures of ASIC1a-psalmotoxin complexes map the toxin binding site to the extracellular domain and show how toxin binding triggers an expansion of the extracellular vestibule and stabilization of the open channel pore. At pH 7.25 the pore is approximately 10 A in diameter, whereas at pH 5.5 the pore is largely hydrophobic and elliptical in cross-section with dimensions of approximately 5 by 7 A, consistent with a barrier mechanism for ion selectivity. These studies define mechanisms for activation of ASICs, illuminate the basis for dynamic ion selectivity and provide the blueprints for new therapeutic agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725952/" 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/PMC3725952/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baconguis, Isabelle -- Gouaux, Eric -- F31 NS070597/NS/NINDS NIH HHS/ -- P30 NS061800/NS/NINDS NIH HHS/ -- R37 NS038631/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Sep 20;489(7416):400-5. doi: 10.1038/nature11375. Epub 2012 Jul 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22842900" target="_blank"〉PubMed〈/a〉
    Keywords: Acid Sensing Ion Channels ; Animals ; Binding Sites ; CHO Cells ; Cations, Monovalent/metabolism ; Cesium/metabolism ; Chickens ; Cricetinae ; Crystallography, X-Ray ; Hydrogen-Ion Concentration ; Ion Channel Gating/*drug effects ; Models, Molecular ; Nerve Tissue Proteins/*chemistry/genetics/*metabolism ; Protein Conformation ; Protein Subunits/chemistry/metabolism ; Sequence Deletion ; Sodium/metabolism/pharmacology ; Sodium Channels/*chemistry/genetics/*metabolism ; Spider Venoms/*chemistry/metabolism/*pharmacology ; Spiders/chemistry ; Substrate Specificity/drug effects
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Structural insight into the type-II mitochondrial NADH dehydrogenases (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-23
    Description: The single-component type-II NADH dehydrogenases (NDH-2s) serve as alternatives to the multisubunit respiratory complex I (type-I NADH dehydrogenase (NDH-1), also called NADH:ubiquinone oxidoreductase; EC 1.6.5.3) in catalysing electron transfer from NADH to ubiquinone in the mitochondrial respiratory chain. The yeast NDH-2 (Ndi1) oxidizes NADH on the matrix side and reduces ubiquinone to maintain mitochondrial NADH/NAD(+) homeostasis. Ndi1 is a potential therapeutic agent for human diseases caused by complex I defects, particularly Parkinson's disease, because its expression restores the mitochondrial activity in animals with complex I deficiency. NDH-2s in pathogenic microorganisms are viable targets for new antibiotics. Here we solve the crystal structures of Ndi1 in its substrate-free, NADH-, ubiquinone- and NADH-ubiquinone-bound states, to help understand the catalytic mechanism of NDH-2s. We find that Ndi1 homodimerization through its carboxy-terminal domain is critical for its catalytic activity and membrane targeting. The structures reveal two ubiquinone-binding sites (UQ(I) and UQ(II)) in Ndi1. NADH and UQ(I) can bind to Ndi1 simultaneously to form a substrate-protein complex. We propose that UQ(I) interacts with FAD to act as an intermediate for electron transfer, and that NADH transfers electrons through this FAD-UQ(I) complex to UQ(II). Together our data reveal the regulatory and catalytic mechanisms of Ndi1 and may facilitate the development or targeting of NDH-2s for potential therapeutic applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Feng, Yue -- Li, Wenfei -- Li, Jian -- Wang, Jiawei -- Ge, Jingpeng -- Xu, Duo -- Liu, Yanjing -- Wu, Kaiqi -- Zeng, Qingyin -- Wu, Jia-Wei -- Tian, Changlin -- Zhou, Bing -- Yang, Maojun -- England -- Nature. 2012 Nov 15;491(7424):478-82. doi: 10.1038/nature11541. Epub 2012 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua-Peking Center for Life Sciences, 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/23086143" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Electron Transport Complex I/*chemistry/isolation & purification/metabolism ; Mitochondria/*enzymology ; *Models, Molecular ; NAD/chemistry ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/chemistry/enzymology ; Saccharomyces cerevisiae Proteins/*chemistry/isolation & purification/metabolism ; Ubiquinone/chemistry
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  • 4
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    Structure of the human kappa-opioid receptor in complex with JDTic (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-23
    Description: Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and--in the case of kappa-opioid receptor (kappa-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human kappa-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 A resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human kappa-OR. Modelling of other important kappa-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for kappa-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human kappa-OR.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356457/" 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/PMC3356457/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Huixian -- Wacker, Daniel -- Mileni, Mauro -- Katritch, Vsevolod -- Han, Gye Won -- Vardy, Eyal -- Liu, Wei -- Thompson, Aaron A -- Huang, Xi-Ping -- Carroll, F Ivy -- Mascarella, S Wayne -- Westkaemper, Richard B -- Mosier, Philip D -- Roth, Bryan L -- Cherezov, Vadim -- Stevens, Raymond C -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073197-08/GM/NIGMS NIH HHS/ -- R01 DA009045/DA/NIDA NIH HHS/ -- R01 DA009045-17/DA/NIDA NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA017624/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54 GM094618-02/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Mar 21;485(7398):327-32. doi: 10.1038/nature10939.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22437504" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Diterpenes, Clerodane/chemistry/metabolism/pharmacology ; Guanidines/chemistry ; Humans ; Models, Molecular ; Morphinans/chemistry ; Mutagenesis, Site-Directed ; Naltrexone/analogs & derivatives/chemistry/metabolism ; Piperidines/*chemistry/pharmacology ; Protein Conformation ; Receptors, Adrenergic, beta-2/chemistry ; Receptors, CXCR4/chemistry/metabolism ; Receptors, Opioid, kappa/*antagonists & inhibitors/*chemistry/genetics/metabolism ; Structure-Activity Relationship ; Tetrahydroisoquinolines/*chemistry/pharmacology
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  • 5
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    Crystal structure of a bacterial homologue of glucose transporters GLUT1-4 (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-19
    Description: Glucose transporters are essential for metabolism of glucose in cells of diverse organisms from microbes to humans, exemplified by the disease-related human proteins GLUT1, 2, 3 and 4. Despite rigorous efforts, the structural information for GLUT1-4 or their homologues remains largely unknown. Here we report three related crystal structures of XylE, an Escherichia coli homologue of GLUT1-4, in complex with d-xylose, d-glucose and 6-bromo-6-deoxy-D-glucose, at resolutions of 2.8, 2.9 and 2.6 A, respectively. The structure consists of a typical major facilitator superfamily fold of 12 transmembrane segments and a unique intracellular four-helix domain. XylE was captured in an outward-facing, partly occluded conformation. Most of the important amino acids responsible for recognition of D-xylose or d-glucose are invariant in GLUT1-4, suggesting functional and mechanistic conservations. Structure-based modelling of GLUT1-4 allows mapping and interpretation of disease-related mutations. The structural and biochemical information reported here constitutes an important framework for mechanistic understanding of glucose transporters and sugar porters in general.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Linfeng -- Zeng, Xin -- Yan, Chuangye -- Sun, Xiuyun -- Gong, Xinqi -- Rao, Yu -- Yan, Nieng -- England -- Nature. 2012 Oct 18;490(7420):361-6. doi: 10.1038/nature11524.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Bio-membrane and Membrane Biotechnology, Center for Structural Biology, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23075985" target="_blank"〉PubMed〈/a〉
    Keywords: Biological Transport ; Crystallography, X-Ray ; Deoxyglucose/analogs & derivatives/chemistry/metabolism ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/metabolism ; Glucose/chemistry/metabolism ; Glucose Transport Proteins, Facilitative/*chemistry/metabolism ; Glucose Transporter Type 1/chemistry ; Humans ; Hydrogen Bonding ; Models, Molecular ; Protein Conformation ; Structural Homology, Protein ; Structure-Activity Relationship ; Substrate Specificity ; Symporters/*chemistry/metabolism ; Xylose/chemistry/metabolism
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  • 6
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    Structure of yeast Argonaute with guide RNA (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-06-23
    Description: The RNA-induced silencing complex, comprising Argonaute and guide RNA, mediates RNA interference. Here we report the 3.2 A crystal structure of Kluyveromyces polysporus Argonaute (KpAGO) fortuitously complexed with guide RNA originating from small-RNA duplexes autonomously loaded by recombinant KpAGO. Despite their diverse sequences, guide-RNA nucleotides 1-8 are positioned similarly, with sequence-independent contacts to bases, phosphates and 2'-hydroxyl groups pre-organizing the backbone of nucleotides 2-8 in a near-A-form conformation. Compared with prokaryotic Argonautes, KpAGO has numerous surface-exposed insertion segments, with a cluster of conserved insertions repositioning the N domain to enable full propagation of guide-target pairing. Compared with Argonautes in inactive conformations, KpAGO has a hydrogen-bond network that stabilizes an expanded and repositioned loop, which inserts an invariant glutamate into the catalytic pocket. Mutation analyses and analogies to ribonuclease H indicate that insertion of this glutamate finger completes a universally conserved catalytic tetrad, thereby activating Argonaute for RNA cleavage.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853139/" 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/PMC3853139/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakanishi, Kotaro -- Weinberg, David E -- Bartel, David P -- Patel, Dinshaw J -- AI068776/AI/NIAID NIH HHS/ -- GM61835/GM/NIGMS NIH HHS/ -- R01 AI068776/AI/NIAID NIH HHS/ -- R01 GM061835/GM/NIGMS NIH HHS/ -- R37 GM061835/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jun 20;486(7403):368-74. doi: 10.1038/nature11211.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722195" target="_blank"〉PubMed〈/a〉
    Keywords: Argonaute Proteins/*chemistry/*metabolism ; Base Sequence ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Eukaryotic Cells/chemistry/enzymology ; Fungal Proteins/*chemistry/*metabolism ; Kluyveromyces/*chemistry/enzymology ; Models, Molecular ; Molecular Conformation ; Molecular Sequence Data ; RNA, Guide/*chemistry/genetics/*metabolism ; Saccharomycetales/enzymology/genetics
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  • 7
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    Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-05-19
    Description: Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, delta, kappa and mu (delta-OR, kappa-OR and mu-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes ( approximately 60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors kappa (ref. 5) and mu (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356928/" 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/PMC3356928/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thompson, Aaron A -- Liu, Wei -- Chun, Eugene -- Katritch, Vsevolod -- Wu, Huixian -- Vardy, Eyal -- Huang, Xi-Ping -- Trapella, Claudio -- Guerrini, Remo -- Calo, Girolamo -- Roth, Bryan L -- Cherezov, Vadim -- Stevens, Raymond C -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073197-08/GM/NIGMS NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA017204-08/DA/NIDA NIH HHS/ -- R01 DA027170/DA/NIDA NIH HHS/ -- R01 DA027170-03/DA/NIDA NIH HHS/ -- R01 DA27170/DA/NIDA NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54 GM094618-02/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 May 16;485(7398):395-9. doi: 10.1038/nature11085.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22596163" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Biomimetic Materials/*chemistry/metabolism/pharmacology ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Ligands ; Models, Molecular ; Narcotic Antagonists ; Opioid Peptides/*chemistry/metabolism/pharmacology ; Piperidines/*chemistry/*metabolism/pharmacology ; Protein Conformation ; Receptors, Opioid/*chemistry/*metabolism ; Receptors, Opioid, kappa/chemistry/metabolism ; Spiro Compounds/*chemistry/*metabolism/pharmacology ; Substrate Specificity
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  • 8
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    Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-06-09
    Description: Voltage-gated sodium (Na(v)) channels are essential for the rapid depolarization of nerve and muscle, and are important drug targets. Determination of the structures of Na(v) channels will shed light on ion channel mechanisms and facilitate potential clinical applications. A family of bacterial Na(v) channels, exemplified by the Na(+)-selective channel of bacteria (NaChBac), provides a useful model system for structure-function analysis. Here we report the crystal structure of Na(v)Rh, a NaChBac orthologue from the marine alphaproteobacterium HIMB114 (Rickettsiales sp. HIMB114; denoted Rh), at 3.05 A resolution. The channel comprises an asymmetric tetramer. The carbonyl oxygen atoms of Thr 178 and Leu 179 constitute an inner site within the selectivity filter where a hydrated Ca(2+) resides in the crystal structure. The outer mouth of the Na(+) selectivity filter, defined by Ser 181 and Glu 183, is closed, as is the activation gate at the intracellular side of the pore. The voltage sensors adopt a depolarized conformation in which all the gating charges are exposed to the extracellular environment. We propose that Na(v)Rh is in an 'inactivated' conformation. Comparison of Na(v)Rh with Na(v)Ab reveals considerable conformational rearrangements that may underlie the electromechanical coupling mechanism of voltage-gated channels.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979295/" 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/PMC3979295/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Xu -- Ren, Wenlin -- DeCaen, Paul -- Yan, Chuangye -- Tao, Xiao -- Tang, Lin -- Wang, Jingjing -- Hasegawa, Kazuya -- Kumasaka, Takashi -- He, Jianhua -- Wang, Jiawei -- Clapham, David E -- Yan, Nieng -- P01 NS072040/NS/NINDS NIH HHS/ -- T32 HL007572/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 20;486(7401):130-4. doi: 10.1038/nature11054.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Bio-membrane and Membrane Biotechnology, Center for Structural Biology, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22678295" target="_blank"〉PubMed〈/a〉
    Keywords: Alphaproteobacteria/*chemistry ; Amino Acid Sequence ; Bacterial Proteins/*chemistry/metabolism ; Crystallization ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; *Ion Channel Gating ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Sodium Channels/*chemistry/metabolism ; Structure-Activity Relationship
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  • 9
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    The same pocket in menin binds both MLL and JUND but has opposite effects on transcription (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-02-14
    Description: Menin is a tumour suppressor protein whose loss or inactivation causes multiple endocrine neoplasia 1 (MEN1), a hereditary autosomal dominant tumour syndrome that is characterized by tumorigenesis in multiple endocrine organs. Menin interacts with many proteins and is involved in a variety of cellular processes. Menin binds the JUN family transcription factor JUND and inhibits its transcriptional activity. Several MEN1 missense mutations disrupt the menin-JUND interaction, suggesting a correlation between the tumour-suppressor function of menin and its suppression of JUND-activated transcription. Menin also interacts with mixed lineage leukaemia protein 1 (MLL1), a histone H3 lysine 4 methyltransferase, and functions as an oncogenic cofactor to upregulate gene transcription and promote MLL1-fusion-protein-induced leukaemogenesis. A recent report on the tethering of MLL1 to chromatin binding factor lens epithelium-derived growth factor (LEDGF) by menin indicates that menin is a molecular adaptor coordinating the functions of multiple proteins. Despite its importance, how menin interacts with many distinct partners and regulates their functions remains poorly understood. Here we present the crystal structures of human menin in its free form and in complexes with MLL1 or with JUND, or with an MLL1-LEDGF heterodimer. These structures show that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983792/" 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/PMC3983792/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Jing -- Gurung, Buddha -- Wan, Bingbing -- Matkar, Smita -- Veniaminova, Natalia A -- Wan, Ke -- Merchant, Juanita L -- Hua, Xianxin -- Lei, Ming -- GM083015-01/GM/NIGMS NIH HHS/ -- R01 DK085121/DK/NIDDK NIH HHS/ -- R01-DK085121/DK/NIDDK NIH HHS/ -- R37 DK045729/DK/NIDDK NIH HHS/ -- R37-DK45729/DK/NIDDK NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 12;482(7386):542-6. doi: 10.1038/nature10806.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22327296" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Binding Sites ; Chromatin/metabolism ; Crystallography, X-Ray ; Fibroblasts ; HEK293 Cells ; Histone-Lysine N-Methyltransferase ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mice ; Models, Molecular ; Molecular Sequence Data ; Myeloid-Lymphoid Leukemia Protein/chemistry/*metabolism ; Phosphorylation ; Protein Binding ; Protein Multimerization ; Proto-Oncogene Proteins/*chemistry/*metabolism ; Proto-Oncogene Proteins c-jun/chemistry/*metabolism ; Structure-Activity Relationship ; *Transcription, Genetic
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    The Shigella flexneri effector OspI deamidates UBC13 to dampen the inflammatory response (2012)
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    Publication Date: 2012-03-13
    Description: Many bacterial pathogens can enter various host cells and then survive intracellularly, transiently evade humoral immunity, and further disseminate to other cells and tissues. When bacteria enter host cells and replicate intracellularly, the host cells sense the invading bacteria as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) by way of various pattern recognition receptors. As a result, the host cells induce alarm signals that activate the innate immune system. Therefore, bacteria must modulate host inflammatory signalling and dampen these alarm signals. How pathogens do this after invading epithelial cells remains unclear, however. Here we show that OspI, a Shigella flexneri effector encoded by ORF169b on the large plasmid and delivered by the type IotaIotaIota secretion system, dampens acute inflammatory responses during bacterial invasion by suppressing the tumour-necrosis factor (TNF)-receptor-associated factor 6 (TRAF6)-mediated signalling pathway. OspI is a glutamine deamidase that selectively deamidates the glutamine residue at position 100 in UBC13 to a glutamic acid residue. Consequently, the E2 ubiquitin-conjugating activity required for TRAF6 activation is inhibited, allowing S. flexneri OspI to modulate the diacylglycerol-CBM (CARD-BCL10-MALT1) complex-TRAF6-nuclear-factor-kappaB signalling pathway. We determined the 2.0 A crystal structure of OspI, which contains a putative cysteine-histidine-aspartic acid catalytic triad. A mutational analysis showed this catalytic triad to be essential for the deamidation of UBC13. Our results suggest that S. flexneri inhibits acute inflammatory responses in the initial stage of infection by targeting the UBC13-TRAF6 complex.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanada, Takahito -- Kim, Minsoo -- Mimuro, Hitomi -- Suzuki, Masato -- Ogawa, Michinaga -- Oyama, Akiho -- Ashida, Hiroshi -- Kobayashi, Taira -- Koyama, Tomohiro -- Nagai, Shinya -- Shibata, Yuri -- Gohda, Jin -- Inoue, Jun-ichiro -- Mizushima, Tsunehiro -- Sasakawa, Chihiro -- England -- Nature. 2012 Mar 11;483(7391):623-6. doi: 10.1038/nature10894.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Infectious Disease Control, International Research Center for Infectious Diseases, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22407319" target="_blank"〉PubMed〈/a〉
    Keywords: *Adaptor Proteins, Signal Transducing/metabolism ; Amidohydrolases/*chemistry/genetics/*metabolism ; Amino Acid Sequence ; Animals ; Aspartic Acid/metabolism ; Biocatalysis ; Caspases/metabolism ; Catalytic Domain/genetics ; Crystallography, X-Ray ; Cysteine/metabolism ; DNA Mutational Analysis ; Diglycerides/antagonists & inhibitors/metabolism ; Dysentery, Bacillary/microbiology ; Glutamic Acid/metabolism ; Glutamine/metabolism ; HEK293 Cells ; HeLa Cells ; Histidine/metabolism ; Humans ; Immunity, Innate ; Inflammation/enzymology/*immunology/*metabolism ; Mice ; Models, Molecular ; Molecular Sequence Data ; NF-kappa B/metabolism ; Neoplasm Proteins/metabolism ; Shigella flexneri/*enzymology/genetics/*immunology/pathogenicity ; TNF Receptor-Associated Factor 6/deficiency/genetics/metabolism ; Ubiquitin-Conjugating Enzymes/chemistry/genetics/*metabolism ; Virulence Factors/metabolism
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    High-resolution crystal structure of human protease-activated receptor 1 (2012)
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    Publication Date: 2012-12-12
    Description: Protease-activated receptor 1 (PAR1) is the prototypical member of a family of G-protein-coupled receptors that mediate cellular responses to thrombin and related proteases. Thrombin irreversibly activates PAR1 by cleaving the amino-terminal exodomain of the receptor, which exposes a tethered peptide ligand that binds the heptahelical bundle of the receptor to affect G-protein activation. Here we report the 2.2 A resolution crystal structure of human PAR1 bound to vorapaxar, a PAR1 antagonist. The structure reveals an unusual mode of drug binding that explains how a small molecule binds virtually irreversibly to inhibit receptor activation by the tethered ligand of PAR1. In contrast to deep, solvent-exposed binding pockets observed in other peptide-activated G-protein-coupled receptors, the vorapaxar-binding pocket is superficial but has little surface exposed to the aqueous solvent. Protease-activated receptors are important targets for drug development. The structure reported here will aid the development of improved PAR1 antagonists and the discovery of antagonists to other members of this receptor family.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531875/" 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/PMC3531875/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Cheng -- Srinivasan, Yoga -- Arlow, Daniel H -- Fung, Juan Jose -- Palmer, Daniel -- Zheng, Yaowu -- Green, Hillary F -- Pandey, Anjali -- Dror, Ron O -- Shaw, David E -- Weis, William I -- Coughlin, Shaun R -- Kobilka, Brian K -- HL44907/HL/NHLBI NIH HHS/ -- HL65590/HL/NHLBI NIH HHS/ -- NS028471/NS/NINDS NIH HHS/ -- R01 HL044907/HL/NHLBI NIH HHS/ -- R01 HL065185/HL/NHLBI NIH HHS/ -- R01 HL065590/HL/NHLBI NIH HHS/ -- England -- Nature. 2012 Dec 20;492(7429):387-92. doi: 10.1038/nature11701. Epub 2012 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23222541" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Binding Sites ; Crystallization ; Crystallography, X-Ray ; Enzyme Activation/genetics ; Humans ; Hydrolysis ; Lactones/chemistry/pharmacology ; Ligands ; Models, Molecular ; Molecular Dynamics Simulation ; Myocardial Infarction/prevention & control ; Protein Conformation ; Pyridines/chemistry/pharmacology ; Receptor, PAR-1/agonists/antagonists & inhibitors/*chemistry/metabolism ; Receptors, G-Protein-Coupled/chemistry/classification ; Receptors, Thrombin
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  • 12
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    Structural basis for iron piracy by pathogenic Neisseria (2012)
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    Publication Date: 2012-02-14
    Description: Neisseria are obligate human pathogens causing bacterial meningitis, septicaemia and gonorrhoea. Neisseria require iron for survival and can extract it directly from human transferrin for transport across the outer membrane. The transport system consists of TbpA, an integral outer membrane protein, and TbpB, a co-receptor attached to the cell surface; both proteins are potentially important vaccine and therapeutic targets. Two key questions driving Neisseria research are how human transferrin is specifically targeted, and how the bacteria liberate iron from transferrin at neutral pH. To address these questions, we solved crystal structures of the TbpA-transferrin complex and of the corresponding co-receptor TbpB. We characterized the TbpB-transferrin complex by small-angle X-ray scattering and the TbpA-TbpB-transferrin complex by electron microscopy. Our studies provide a rational basis for the specificity of TbpA for human transferrin, show how TbpA promotes iron release from transferrin, and elucidate how TbpB facilitates this process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292680/" 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/PMC3292680/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Noinaj, Nicholas -- Easley, Nicole C -- Oke, Muse -- Mizuno, Naoko -- Gumbart, James -- Boura, Evzen -- Steere, Ashley N -- Zak, Olga -- Aisen, Philip -- Tajkhorshid, Emad -- Evans, Robert W -- Gorringe, Andrew R -- Mason, Anne B -- Steven, Alasdair C -- Buchanan, Susan K -- P41 RR005969/RR/NCRR NIH HHS/ -- P41-RR05969/RR/NCRR NIH HHS/ -- R01 GM086749/GM/NIGMS NIH HHS/ -- R01-DK21739/DK/NIDDK NIH HHS/ -- R01-GM086749/GM/NIGMS NIH HHS/ -- U54 GM087519/GM/NIGMS NIH HHS/ -- U54-GM087519/GM/NIGMS NIH HHS/ -- ZIA DK036143-04/Intramural NIH HHS/ -- England -- Nature. 2012 Feb 12;483(7387):53-8. doi: 10.1038/nature10823.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22327295" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoproteins/chemistry/metabolism ; Bacterial Proteins/*chemistry/metabolism/ultrastructure ; Binding Sites ; Biological Transport ; Cattle ; Crystallography, X-Ray ; Humans ; Iron/*metabolism ; Mice ; Models, Molecular ; Molecular Dynamics Simulation ; Neisseria/*metabolism/pathogenicity ; Protein Conformation ; Scattering, Small Angle ; Species Specificity ; Structure-Activity Relationship ; Transferrin/chemistry/metabolism/ultrastructure ; Transferrin-Binding Protein A/*chemistry/*metabolism/ultrastructure ; Transferrin-Binding Protein B/*chemistry/*metabolism/ultrastructure ; X-Ray Diffraction
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  • 13
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    Structural insights into electron transfer in caa3-type cytochrome oxidase (2012)
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    Publication Date: 2012-07-06
    Description: Cytochrome c oxidase is a member of the haem copper oxidase superfamily (HCO). HCOs function as the terminal enzymes in the respiratory chain of mitochondria and aerobic prokaryotes, coupling molecular oxygen reduction to transmembrane proton pumping. Integral to the enzyme's function is the transfer of electrons from cytochrome c to the oxidase via a transient association of the two proteins. Electron entry and exit are proposed to occur from the same site on cytochrome c. Here we report the crystal structure of the caa3-type cytochrome oxidase from Thermus thermophilus, which has a covalently tethered cytochrome c domain. Crystals were grown in a bicontinuous mesophase using a synthetic short-chain monoacylglycerol as the hosting lipid. From the electron density map, at 2.36 A resolution, a novel integral membrane subunit and a native glycoglycerophospholipid embedded in the complex were identified. Contrary to previous electron transfer mechanisms observed for soluble cytochrome c, the structure reveals the architecture of the electron transfer complex for the fused cupredoxin/cytochrome c domain, which implicates different sites on cytochrome c for electron entry and exit. Support for an alternative to the classical proton gate characteristic of this HCO class is presented.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428721/" 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/PMC3428721/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lyons, Joseph A -- Aragao, David -- Slattery, Orla -- Pisliakov, Andrei V -- Soulimane, Tewfik -- Caffrey, Martin -- GM75915/GM/NIGMS NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- P50GM073210/GM/NIGMS NIH HHS/ -- R01 GM061070/GM/NIGMS NIH HHS/ -- R01 GM075915/GM/NIGMS NIH HHS/ -- U54 GM094599/GM/NIGMS NIH HHS/ -- U54GM094599/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Jul 26;487(7408):514-8. doi: 10.1038/nature11182.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical and Environmental Sciences, University of Limerick, Limerick, Ireland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763450" target="_blank"〉PubMed〈/a〉
    Keywords: Azurin/metabolism ; Catalytic Domain ; Cell Membrane/metabolism ; Crystallization ; Crystallography, X-Ray ; Cytochrome c Group/*metabolism ; Cytochromes a/*metabolism ; Cytochromes a3/*metabolism ; Electron Transport ; Electron Transport Complex IV/*chemistry/*metabolism ; Electrons ; Glycerophospholipids/chemistry/metabolism ; Models, Molecular ; Oxygen/metabolism ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Protons ; Thermus thermophilus/*enzymology ; Water/chemistry/metabolism
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  • 14
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    Cell attachment protein VP8* of a human rotavirus specifically interacts with A-type histo-blood group antigen (2012)
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    Publication Date: 2012-04-17
    Description: As with many other viruses, the initial cell attachment of rotaviruses, which are the major causative agent of infantile gastroenteritis, is mediated by interactions with specific cellular glycans. The distally located VP8* domain of the rotavirus spike protein VP4 (ref. 5) mediates such interactions. The existing paradigm is that 'sialidase-sensitive' animal rotavirus strains bind to glycans with terminal sialic acid (Sia), whereas 'sialidase-insensitive' human rotavirus strains bind to glycans with internal Sia such as GM1 (ref. 3). Although the involvement of Sia in the animal strains is firmly supported by crystallographic studies, it is not yet known how VP8* of human rotaviruses interacts with Sia and whether their cell attachment necessarily involves sialoglycans. Here we show that VP8* of a human rotavirus strain specifically recognizes A-type histo-blood group antigen (HBGA) using a glycan array screen comprised of 511 glycans, and that virus infectivity in HT-29 cells is abrogated by anti-A-type antibodies as well as significantly enhanced in Chinese hamster ovary cells genetically modified to express the A-type HBGA, providing a novel paradigm for initial cell attachment of human rotavirus. HBGAs are genetically determined glycoconjugates present in mucosal secretions, epithelia and on red blood cells, and are recognized as susceptibility and cell attachment factors for gastric pathogens like Helicobacter pylori and noroviruses. Our crystallographic studies show that the A-type HBGA binds to the human rotavirus VP8* at the same location as the Sia in the VP8* of animal rotavirus, and suggest how subtle changes within the same structural framework allow for such receptor switching. These results raise the possibility that host susceptibility to specific human rotavirus strains and pathogenesis are influenced by genetically controlled expression of different HBGAs among the world's population.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350622/" 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/PMC3350622/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hu, Liya -- Crawford, Sue E -- Czako, Rita -- Cortes-Penfield, Nicolas W -- Smith, David F -- Le Pendu, Jacques -- Estes, Mary K -- Prasad, B V Venkataram -- AI 080656/AI/NIAID NIH HHS/ -- AI36040/AI/NIAID NIH HHS/ -- GM62116/GM/NIGMS NIH HHS/ -- P30 DK056338/DK/NIDDK NIH HHS/ -- P30 DK56338/DK/NIDDK NIH HHS/ -- P41 GM103694/GM/NIGMS NIH HHS/ -- R01 AI080656/AI/NIAID NIH HHS/ -- U54 GM062116/GM/NIGMS NIH HHS/ -- U54 GM062116-01A1/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Apr 15;485(7397):256-9. doi: 10.1038/nature10996.〈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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22504179" target="_blank"〉PubMed〈/a〉
    Keywords: ABO Blood-Group System/chemistry/genetics/immunology/*metabolism ; Amino Acid Sequence ; Animals ; CHO Cells ; Cricetinae ; Crystallography, X-Ray ; Erythrocytes/metabolism/virology ; Host Specificity/*physiology ; Humans ; Models, Molecular ; Molecular Sequence Data ; N-Acetylneuraminic Acid/antagonists & inhibitors/chemistry/immunology/metabolism ; RNA-Binding Proteins/chemistry/*metabolism ; Receptors, Virus/chemistry/genetics/*metabolism ; *Rotavirus/chemistry/classification/metabolism/pathogenicity ; Viral Nonstructural Proteins/chemistry/*metabolism
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    Identification and characterization of a bacterial hydrosulphide ion channel (2012)
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    Publication Date: 2012-03-13
    Description: The hydrosulphide ion (HS(-)) and its undissociated form, hydrogen sulphide (H(2)S), which are believed to have been critical to the origin of life on Earth, remain important in physiology and cellular signalling. As a major metabolite in anaerobic bacterial growth, hydrogen sulphide is a product of both assimilatory and dissimilatory sulphate reduction. These pathways can reduce various oxidized sulphur compounds including sulphate, sulphite and thiosulphate. The dissimilatory sulphate reduction pathway uses this molecule as the terminal electron acceptor for anaerobic respiration, in which process it produces excess amounts of H(2)S (ref. 4). The reduction of sulphite is a key intermediate step in all sulphate reduction pathways. In Clostridium and Salmonella, an inducible sulphite reductase is directly linked to the regeneration of NAD(+), which has been suggested to have a role in energy production and growth, as well as in the detoxification of sulphite. Above a certain concentration threshold, both H(2)S and HS(-) inhibit cell growth by binding the metal centres of enzymes and cytochrome oxidase, necessitating a release mechanism for the export of this toxic metabolite from the cell. Here we report the identification of a hydrosulphide ion channel in the pathogen Clostridium difficile through a combination of genetic, biochemical and functional approaches. The HS(-) channel is a member of the formate/nitrite transport family, in which about 50 hydrosulphide ion channels form a third subfamily alongside those for formate (FocA) and for nitrite (NirC). The hydrosulphide ion channel is permeable to formate and nitrite as well as to HS(-) ions. Such polyspecificity can be explained by the conserved ion selectivity filter observed in the channel's crystal structure. The channel has a low open probability and is tightly regulated, to avoid decoupling of the membrane proton gradient.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711795/" 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/PMC3711795/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Czyzewski, Bryan K -- Wang, Da-Neng -- F31 AI086072/AI/NIAID NIH HHS/ -- F31-AI086072/AI/NIAID NIH HHS/ -- R01 DK053973/DK/NIDDK NIH HHS/ -- R01 GM093825/GM/NIGMS NIH HHS/ -- R01 MH083840/MH/NIMH NIH HHS/ -- R01-DK053973-08A1S1/DK/NIDDK NIH HHS/ -- R01-DK073973/DK/NIDDK NIH HHS/ -- R01-GM093825/GM/NIGMS NIH HHS/ -- R01-MH083840/MH/NIMH NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54-GM075026/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Mar 11;483(7390):494-7. doi: 10.1038/nature10881.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22407320" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/chemistry/genetics/isolation & purification/metabolism ; *Clostridium difficile/chemistry/drug effects/genetics ; Crystallography, X-Ray ; Formates/metabolism ; Ion Channel Gating ; Ion Channels/chemistry/genetics/*isolation & purification/*metabolism ; Ion Transport ; Models, Biological ; Models, Molecular ; Nitrites/metabolism ; Operon/genetics ; Proteolipids/metabolism ; Proton-Motive Force ; Structure-Activity Relationship ; Substrate Specificity ; Sulfides/*metabolism/toxicity
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    Crystal structure of a voltage-gated sodium channel in two potentially inactivated states (2012)
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    Publication Date: 2012-06-09
    Description: In excitable cells, voltage-gated sodium (Na(V)) channels activate to initiate action potentials and then undergo fast and slow inactivation processes that terminate their ionic conductance. Inactivation is a hallmark of Na(V) channel function and is critical for control of membrane excitability, but the structural basis for this process has remained elusive. Here we report crystallographic snapshots of the wild-type Na(V)Ab channel from Arcobacter butzleri captured in two potentially inactivated states at 3.2 A resolution. Compared to previous structures of Na(V)Ab channels with cysteine mutations in the pore-lining S6 helices (ref. 4), the S6 helices and the intracellular activation gate have undergone significant rearrangements: one pair of S6 helices has collapsed towards the central pore axis and the other S6 pair has moved outward to produce a striking dimer-of-dimers configuration. An increase in global structural asymmetry is observed throughout our wild-type Na(V)Ab models, reshaping the ion selectivity filter at the extracellular end of the pore, the central cavity and its residues that are analogous to the mammalian drug receptor site, and the lateral pore fenestrations. The voltage-sensing domains have also shifted around the perimeter of the pore module in wild-type Na(V)Ab, compared to the mutant channel, and local structural changes identify a conserved interaction network that connects distant molecular determinants involved in Na(V) channel gating and inactivation. These potential inactivated-state structures provide new insights into Na(V) channel gating and novel avenues to drug development and therapy for a range of debilitating Na(V) channelopathies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552482/" 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/PMC3552482/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Payandeh, Jian -- Gamal El-Din, Tamer M -- Scheuer, Todd -- Zheng, Ning -- Catterall, William A -- R01 HL112808/HL/NHLBI NIH HHS/ -- R01 NS015751/NS/NINDS NIH HHS/ -- R01 NS15751/NS/NINDS NIH HHS/ -- U01 NS058039/NS/NINDS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 20;486(7401):135-9. doi: 10.1038/nature11077.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22678296" target="_blank"〉PubMed〈/a〉
    Keywords: Arcobacter/*chemistry ; Conserved Sequence ; Crystallization ; Crystallography, X-Ray ; *Ion Channel Gating ; Models, Molecular ; Protein Conformation ; Sodium Channels/*chemistry/metabolism ; Structure-Activity Relationship
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  • 17
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    Structure and mechanism of a glutamate-GABA antiporter (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-13
    Description: Food-borne hemorrhagic Escherichia coli, exemplified by the strains O157:H7 and O104:H4 (refs 1, 2), require elaborate acid-resistance systems (ARs) to survive the extremely acidic environment such as the stomach (pH approximately 2). AR2 expels intracellular protons through the decarboxylation of L-glutamate (Glu) in the cytoplasm and exchange of the reaction product gamma-aminobutyric acid (GABA) with extracellular Glu. The latter process is mediated by the Glu-GABA antiporter GadC, a representative member of the amino-acid-polyamine-organocation superfamily of membrane transporters. The functional mechanism of GadC remains largely unknown. Here we show, with the use of an in vitro proteoliposome-based assay, that GadC transports GABA/Glu only under acidic conditions, with no detectable activity at pH values higher than 6.5. We determined the crystal structure of E. coli GadC at 3.1 A resolution under basic conditions. GadC, comprising 12 transmembrane segments (TMs), exists in a closed state, with its carboxy-terminal domain serving as a plug to block an otherwise inward-open conformation. Structural and biochemical analyses reveal the essential transport residues, identify the transport path and suggest a conserved transport mechanism involving the rigid-body rotation of a helical bundle for GadC and other amino acid antiporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ma, Dan -- Lu, Peilong -- Yan, Chuangye -- Fan, Chao -- Yin, Ping -- Wang, Jiawei -- Shi, Yigong -- England -- Nature. 2012 Mar 11;483(7391):632-6. doi: 10.1038/nature10917.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ministry of Education Protein Science Laboratory, Center for Structural Biology, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22407317" target="_blank"〉PubMed〈/a〉
    Keywords: Antiporters/*chemistry/*metabolism ; Biological Transport ; Crystallography, X-Ray ; Escherichia coli O157/*chemistry ; Escherichia coli Proteins/*chemistry/*metabolism ; Glutamic Acid/*metabolism ; Membrane Proteins/*chemistry/*metabolism ; Models, Molecular ; Protein Structure, Tertiary ; Proteolipids/metabolism ; Rotation ; Structure-Activity Relationship ; gamma-Aminobutyric Acid/*metabolism
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  • 18
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    B12 cofactors directly stabilize an mRNA regulatory switch (2012)
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    Publication Date: 2012-10-16
    Description: Structures of riboswitch receptor domains bound to their effector have shown how messenger RNAs recognize diverse small molecules, but mechanistic details linking the structures to the regulation of gene expression remain elusive. To address this, here we solve crystal structures of two different classes of cobalamin (vitamin B(12))-binding riboswitches that include the structural switch of the downstream regulatory domain. These classes share a common cobalamin-binding core, but use distinct peripheral extensions to recognize different B(12) derivatives. In each case, recognition is accomplished through shape complementarity between the RNA and cobalamin, with relatively few hydrogen bonding interactions that typically govern RNA-small molecule recognition. We show that a composite cobalamin-RNA scaffold stabilizes an unusual long-range intramolecular kissing-loop interaction that controls mRNA expression. This is the first, to our knowledge, riboswitch crystal structure detailing how the receptor and regulatory domains communicate in a ligand-dependent fashion to regulate mRNA expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518761/" 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/PMC3518761/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johnson, James E Jr -- Reyes, Francis E -- Polaski, Jacob T -- Batey, Robert T -- 1S10RR026516/RR/NCRR NIH HHS/ -- F32 GM095121/GM/NIGMS NIH HHS/ -- F32GM095121/GM/NIGMS NIH HHS/ -- GM073850/GM/NIGMS NIH HHS/ -- R01 GM073850/GM/NIGMS NIH HHS/ -- S10 RR026516/RR/NCRR NIH HHS/ -- England -- Nature. 2012 Dec 6;492(7427):133-7. doi: 10.1038/nature11607. Epub 2012 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309-0596, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23064232" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Calorimetry ; Crystallography, X-Ray ; Escherichia coli/genetics ; Gene Expression Regulation/drug effects ; Hydrogen Bonding/drug effects ; Ligands ; Models, Molecular ; Nucleic Acid Conformation/*drug effects ; RNA, Bacterial/genetics ; RNA, Messenger/*chemistry/drug effects/genetics/metabolism ; Riboswitch/*drug effects/genetics ; Thermodynamics ; Vitamin B 12/*chemistry/metabolism/*pharmacology
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  • 19
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    Crystal structure of the channelrhodopsin light-gated cation channel (2012)
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    Publication Date: 2012-01-24
    Description: Channelrhodopsins (ChRs) are light-gated cation channels derived from algae that have shown experimental utility in optogenetics; for example, neurons expressing ChRs can be optically controlled with high temporal precision within systems as complex as freely moving mammals. Although ChRs have been broadly applied to neuroscience research, little is known about the molecular mechanisms by which these unusual and powerful proteins operate. Here we present the crystal structure of a ChR (a C1C2 chimaera between ChR1 and ChR2 from Chlamydomonas reinhardtii) at 2.3 A resolution. The structure reveals the essential molecular architecture of ChRs, including the retinal-binding pocket and cation conduction pathway. This integration of structural and electrophysiological analyses provides insight into the molecular basis for the remarkable function of ChRs, and paves the way for the precise and principled design of ChR variants with novel properties.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160518/" 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/PMC4160518/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kato, Hideaki E -- Zhang, Feng -- Yizhar, Ofer -- Ramakrishnan, Charu -- Nishizawa, Tomohiro -- Hirata, Kunio -- Ito, Jumpei -- Aita, Yusuke -- Tsukazaki, Tomoya -- Hayashi, Shigehiko -- Hegemann, Peter -- Maturana, Andres D -- Ishitani, Ryuichiro -- Deisseroth, Karl -- Nureki, Osamu -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 22;482(7385):369-74. doi: 10.1038/nature10870.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22266941" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacteriorhodopsins/chemistry ; Binding Sites ; Cations/*metabolism ; Cattle ; Chlamydomonas reinhardtii/*chemistry/genetics ; Crystallography, X-Ray ; Ion Channel Gating/*radiation effects ; Ion Channels/*chemistry/genetics/radiation effects ; *Light ; Models, Molecular ; Mutation ; Protein Conformation ; Recombinant Fusion Proteins/chemistry/genetics/radiation effects ; Retinaldehyde/metabolism ; Rhodopsin/*chemistry/genetics/radiation effects ; Schiff Bases/chemistry ; Static Electricity
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    Opioid receptors revealed (2012)
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    Publication Date: 2012-03-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buchen, Lizzie -- England -- Nature. 2012 Mar 21;483(7390):383. doi: 10.1038/483383a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22437584" target="_blank"〉PubMed〈/a〉
    Keywords: Analgesics, Opioid/pharmacology ; Crystallization/methods ; Crystallography, X-Ray ; Models, Molecular ; Narcotic Antagonists ; Receptors, Opioid/agonists/*chemistry
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  • 21
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    Structure and mechanism of a bacterial sodium-dependent dicarboxylate transporter (2012)
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    Publication Date: 2012-10-23
    Description: In human cells, cytosolic citrate is a chief precursor for the synthesis of fatty acids, triacylglycerols, cholesterol and low-density lipoprotein. Cytosolic citrate further regulates the energy balance of the cell by activating the fatty-acid-synthesis pathway while downregulating both the glycolysis and fatty-acid beta-oxidation pathways. The rate of fatty-acid synthesis in liver and adipose cells, the two main tissue types for such synthesis, correlates directly with the concentration of citrate in the cytosol, with the cytosolic citrate concentration partially depending on direct import across the plasma membrane through the Na(+)-dependent citrate transporter (NaCT). Mutations of the homologous fly gene (Indy; I'm not dead yet) result in reduced fat storage through calorie restriction. More recently, Nact (also known as Slc13a5)-knockout mice have been found to have increased hepatic mitochondrial biogenesis, higher lipid oxidation and energy expenditure, and reduced lipogenesis, which taken together protect the mice from obesity and insulin resistance. To understand the transport mechanism of NaCT and INDY proteins, here we report the 3.2 A crystal structure of a bacterial INDY homologue. One citrate molecule and one sodium ion are bound per protein, and their binding sites are defined by conserved amino acid motifs, forming the structural basis for understanding the specificity of the transporter. Comparison of the structures of the two symmetrical halves of the transporter suggests conformational changes that propel substrate translocation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617922/" 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/PMC3617922/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mancusso, Romina -- Gregorio, G Glenn -- Liu, Qun -- Wang, Da-Neng -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 DK053973/DK/NIDDK NIH HHS/ -- R01 GM093825/GM/NIGMS NIH HHS/ -- R01 MH083840/MH/NIMH NIH HHS/ -- R01-DK073973/DK/NIDDK NIH HHS/ -- R01-GM093825/GM/NIGMS NIH HHS/ -- R01-MH083840/MH/NIMH NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- U54-GM075026/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 22;491(7425):622-6. doi: 10.1038/nature11542. Epub 2012 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23086149" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Binding Sites ; Citric Acid/chemistry/metabolism ; Crystallography, X-Ray ; Dicarboxylic Acid Transporters/*chemistry/*metabolism ; Ion Transport ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; Sodium/chemistry/metabolism ; Structural Homology, Protein ; Structure-Activity Relationship ; Vibrio cholerae/*chemistry
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    Structure of the delta-opioid receptor bound to naltrindole (2012)
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    Publication Date: 2012-05-19
    Description: The opioid receptor family comprises three members, the micro-, delta- and kappa-opioid receptors, which respond to classical opioid alkaloids such as morphine and heroin as well as to endogenous peptide ligands like endorphins. They belong to the G-protein-coupled receptor (GPCR) superfamily, and are excellent therapeutic targets for pain control. The delta-opioid receptor (delta-OR) has a role in analgesia, as well as in other neurological functions that remain poorly understood. The structures of the micro-OR and kappa-OR have recently been solved. Here we report the crystal structure of the mouse delta-OR, bound to the subtype-selective antagonist naltrindole. Together with the structures of the micro-OR and kappa-OR, the delta-OR structure provides insights into conserved elements of opioid ligand recognition while also revealing structural features associated with ligand-subtype selectivity. The binding pocket of opioid receptors can be divided into two distinct regions. Whereas the lower part of this pocket is highly conserved among opioid receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the 'message-address' model of opioid receptor pharmacology, in which distinct 'message' (efficacy) and 'address' (selectivity) determinants are contained within a single ligand. Comparison of the address region of the delta-OR with other GPCRs reveals that this structural organization may be a more general phenomenon, extending to other GPCR families as well.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523198/" 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/PMC3523198/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Granier, Sebastien -- Manglik, Aashish -- Kruse, Andrew C -- Kobilka, Tong Sun -- Thian, Foon Sun -- Weis, William I -- Kobilka, Brian K -- DA031418/DA/NIDA NIH HHS/ -- NS028471/NS/NINDS NIH HHS/ -- R01 GM083118/GM/NIGMS NIH HHS/ -- R01 NS028471/NS/NINDS NIH HHS/ -- R21 DA031418/DA/NIDA NIH HHS/ -- England -- Nature. 2012 May 16;485(7398):400-4. doi: 10.1038/nature11111.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA. granier@stanford.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22596164" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; Conserved Sequence ; Crystallography, X-Ray ; Mice ; Models, Molecular ; Molecular Sequence Data ; Naltrexone/*analogs & derivatives/chemistry/metabolism/pharmacology ; Protein Structure, Tertiary ; Receptors, Opioid, delta/antagonists & inhibitors/*chemistry/metabolism ; Reproducibility of Results ; Structure-Activity Relationship ; Substrate Specificity
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    Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist (2012)
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    Publication Date: 2012-01-27
    Description: The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345277/" 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/PMC3345277/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haga, Kazuko -- Kruse, Andrew C -- Asada, Hidetsugu -- Yurugi-Kobayashi, Takami -- Shiroishi, Mitsunori -- Zhang, Cheng -- Weis, William I -- Okada, Tetsuji -- Kobilka, Brian K -- Haga, Tatsuya -- Kobayashi, Takuya -- GM083118/GM/NIGMS NIH HHS/ -- NS028471/NS/NINDS NIH HHS/ -- R01 NS028471/NS/NINDS NIH HHS/ -- R37 NS028471/NS/NINDS NIH HHS/ -- R37 NS028471-21/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Jan 25;482(7386):547-51. doi: 10.1038/nature10753.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Life Science, Faculty of Science, Gakushuin University, Mejiro 1-5-1, Tokyo 171-8588, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22278061" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylcholine/analogs & derivatives/chemistry/metabolism ; Acetylcholinesterase/chemistry/metabolism ; Allosteric Regulation ; Binding Sites ; Carrier Proteins/chemistry/metabolism ; Cholinergic Antagonists/*chemistry/metabolism/*pharmacology ; Crystallography, X-Ray ; Evolution, Molecular ; Humans ; Ligands ; Models, Molecular ; Protein Conformation ; Quinuclidinyl Benzilate/*analogs & ; derivatives/*chemistry/metabolism/*pharmacology ; Receptor, Muscarinic M2/*antagonists & inhibitors/*chemistry/genetics/metabolism ; Tyrosine/chemistry/metabolism
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    Structure of the proton-gated urea channel from the gastric pathogen Helicobacter pylori (2012)
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    Publication Date: 2012-12-12
    Description: Half the world's population is chronically infected with Helicobacter pylori, causing gastritis, gastric ulcers and an increased incidence of gastric adenocarcinoma. Its proton-gated inner-membrane urea channel, HpUreI, is essential for survival in the acidic environment of the stomach. The channel is closed at neutral pH and opens at acidic pH to allow the rapid access of urea to cytoplasmic urease. Urease produces NH(3) and CO(2), neutralizing entering protons and thus buffering the periplasm to a pH of roughly 6.1 even in gastric juice at a pH below 2.0. Here we report the structure of HpUreI, revealing six protomers assembled in a hexameric ring surrounding a central bilayer plug of ordered lipids. Each protomer encloses a channel formed by a twisted bundle of six transmembrane helices. The bundle defines a previously unobserved fold comprising a two-helix hairpin motif repeated three times around the central axis of the channel, without the inverted repeat of mammalian-type urea transporters. Both the channel and the protomer interface contain residues conserved in the AmiS/UreI superfamily, suggesting the preservation of channel architecture and oligomeric state in this superfamily. Predominantly aromatic or aliphatic side chains line the entire channel and define two consecutive constriction sites in the middle of the channel. Mutation of Trp 153 in the cytoplasmic constriction site to Ala or Phe decreases the selectivity for urea in comparison with thiourea, suggesting that solute interaction with Trp 153 contributes specificity. The previously unobserved hexameric channel structure described here provides a new model for the permeation of urea and other small amide solutes in prokaryotes and archaea.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974264/" 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/PMC3974264/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Strugatsky, David -- McNulty, Reginald -- Munson, Keith -- Chen, Chiung-Kuang -- Soltis, S Michael -- Sachs, George -- Luecke, Hartmut -- 5T32CA9054-34/CA/NCI NIH HHS/ -- P30CA062203/CA/NCI NIH HHS/ -- P41RR001209/RR/NCRR NIH HHS/ -- R01 AI078000/AI/NIAID NIH HHS/ -- R01AI78000/AI/NIAID NIH HHS/ -- R01DK53462/DK/NIDDK NIH HHS/ -- R01DK58333/DK/NIDDK NIH HHS/ -- T32 CA009054/CA/NCI NIH HHS/ -- England -- Nature. 2013 Jan 10;493(7431):255-8. doi: 10.1038/nature11684. Epub 2012 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉David Geffen School of Medicine, University of California Los Angeles, Greater West Los Angeles Health Care System, Los Angeles, California 90073, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23222544" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Bacterial Proteins/*chemistry/*metabolism ; Crystallography, X-Ray ; Helicobacter pylori/*chemistry ; Hydrogen-Ion Concentration ; Models, Molecular ; Protein Multimerization ; Protein Structure, Secondary ; *Protons ; Structural Homology, Protein ; Urea/*metabolism
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    Structure and function of the initially transcribing RNA polymerase II-TFIIB complex (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-11-16
    Description: The general transcription factor (TF) IIB is required for RNA polymerase (Pol) II initiation and extends with its B-reader element into the Pol II active centre cleft. Low-resolution structures of the Pol II-TFIIB complex indicated how TFIIB functions in DNA recruitment, but they lacked nucleic acids and half of the B-reader, leaving other TFIIB functions enigmatic. Here we report crystal structures of the Pol II-TFIIB complex from the yeast Saccharomyces cerevisiae at 3.4 A resolution and of an initially transcribing complex that additionally contains the DNA template and a 6-nucleotide RNA product. The structures reveal the entire B-reader and protein-nucleic acid interactions, and together with functional data lead to a more complete understanding of transcription initiation. TFIIB partially closes the polymerase cleft to position DNA and assist in its opening. The B-reader does not reach the active site but binds the DNA template strand upstream to assist in the recognition of the initiator sequence and in positioning the transcription start site. TFIIB rearranges active-site residues, induces binding of the catalytic metal ion B, and stimulates initial RNA synthesis allosterically. TFIIB then prevents the emerging DNA-RNA hybrid duplex from tilting, which would impair RNA synthesis. When the RNA grows beyond 6 nucleotides, it is separated from DNA and is directed to its exit tunnel by the B-reader loop. Once the RNA grows to 12-13 nucleotides, it clashes with TFIIB, triggering TFIIB displacement and elongation complex formation. Similar mechanisms may underlie all cellular transcription because all eukaryotic and archaeal RNA polymerases use TFIIB-like factors, and the bacterial initiation factor sigma has TFIIB-like topology and contains the loop region 3.2 that resembles the B-reader loop in location, charge and function. TFIIB and its counterparts may thus account for the two fundamental properties that distinguish RNA from DNA polymerases: primer-independent chain initiation and product separation from the template.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sainsbury, Sarah -- Niesser, Jurgen -- Cramer, Patrick -- England -- Nature. 2013 Jan 17;493(7432):437-40. doi: 10.1038/nature11715. Epub 2012 Nov 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Center and Department of Biochemistry, Center for Integrated Protein Science CIPSM, Ludwig-Maximilians-Universitat Munchen, Feodor-Lynen-Str. 25, 81377 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23151482" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Biocatalysis ; Crystallography, X-Ray ; DNA/genetics/metabolism ; Models, Molecular ; Molecular Sequence Data ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; RNA Polymerase II/*chemistry/*metabolism ; RNA, Messenger/biosynthesis/metabolism ; Saccharomyces cerevisiae/enzymology ; Structure-Activity Relationship ; Templates, Genetic ; Transcription Factor TFIIB/*chemistry/*metabolism ; *Transcription Initiation, Genetic
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    The dynamic disulphide relay of quiescin sulphydryl oxidase (2012)
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    Publication Date: 2012-07-18
    Description: Protein stability, assembly, localization and regulation often depend on the formation of disulphide crosslinks between cysteine side chains. Enzymes known as sulphydryl oxidases catalyse de novo disulphide formation and initiate intra- and intermolecular dithiol/disulphide relays to deliver the disulphides to substrate proteins. Quiescin sulphydryl oxidase (QSOX) is a unique, multi-domain disulphide catalyst that is localized primarily to the Golgi apparatus and secreted fluids and has attracted attention owing to its overproduction in tumours. In addition to its physiological importance, QSOX is a mechanistically intriguing enzyme, encompassing functions typically carried out by a series of proteins in other disulphide-formation pathways. How disulphides are relayed through the multiple redox-active sites of QSOX and whether there is a functional benefit to concatenating these sites on a single polypeptide are open questions. Here we present the first crystal structure of an intact QSOX enzyme, derived from a trypanosome parasite. Notably, sequential sites in the disulphide relay were found more than 40 A apart in this structure, too far for direct disulphide transfer. To resolve this puzzle, we trapped and crystallized an intermediate in the disulphide hand-off, which showed a 165 degrees domain rotation relative to the original structure, bringing the two active sites within disulphide-bonding distance. The comparable structure of a mammalian QSOX enzyme, also presented here, shows further biochemical features that facilitate disulphide transfer in metazoan orthologues. Finally, we quantified the contribution of concatenation to QSOX activity, providing general lessons for the understanding of multi-domain enzymes and the design of new catalytic relays.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521037/" 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/PMC3521037/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alon, Assaf -- Grossman, Iris -- Gat, Yair -- Kodali, Vamsi K -- DiMaio, Frank -- Mehlman, Tevie -- Haran, Gilad -- Baker, David -- Thorpe, Colin -- Fass, Deborah -- GM26643/GM/NIGMS NIH HHS/ -- P41 RR001081/RR/NCRR NIH HHS/ -- R01 GM026643/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Aug 16;488(7411):414-8. doi: 10.1038/nature11267.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22801504" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Disulfides/*metabolism ; Humans ; Mice ; Models, Molecular ; Oxidation-Reduction ; Oxidoreductases/*chemistry/*metabolism ; Protein Conformation ; Rotation ; Trypanosoma brucei brucei/*enzymology
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    Structure of HDAC3 bound to co-repressor and inositol tetraphosphate (2012)
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    Publication Date: 2012-01-11
    Description: Histone deacetylase enzymes (HDACs) are emerging cancer drug targets. They regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation. The enzymatic activity of most class I HDACs requires recruitment into multi-subunit co-repressor complexes, which are in turn recruited to chromatin by repressive transcription factors. Here we report the structure of a complex between an HDAC and a co-repressor, namely, human HDAC3 with the deacetylase activation domain (DAD) from the human SMRT co-repressor (also known as NCOR2). The structure reveals two remarkable features. First, the SMRT-DAD undergoes a large structural rearrangement on forming the complex. Second, there is an essential inositol tetraphosphate molecule--D-myo-inositol-(1,4,5,6)-tetrakisphosphate (Ins(1,4,5,6)P(4))--acting as an 'intermolecular glue' between the two proteins. Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P(4), which may act as a regulator--potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators. This mechanism for the activation of HDAC3 appears to be conserved in class I HDACs from yeast to humans, and opens the way to novel therapeutic opportunities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272448/" 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/PMC3272448/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watson, Peter J -- Fairall, Louise -- Santos, Guilherme M -- Schwabe, John W R -- 085408/Wellcome Trust/United Kingdom -- 100237/Wellcome Trust/United Kingdom -- WT085408/Wellcome Trust/United Kingdom -- England -- Nature. 2012 Jan 9;481(7381):335-40. doi: 10.1038/nature10728.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Henry Wellcome Laboratories of Structural Biology, Department of Biochemistry, University of Leicester, Leicester LE1 9HN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22230954" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Conserved Sequence ; Crystallography, X-Ray ; Enzyme Activation/drug effects ; Histone Deacetylases/*chemistry/*metabolism ; Humans ; Inositol Phosphates/*chemistry/*metabolism/pharmacology ; Models, Molecular ; Molecular Sequence Data ; Molecular Targeted Therapy ; Multiprotein Complexes/chemistry/metabolism ; Nuclear Receptor Co-Repressor 2/*chemistry ; Protein Multimerization/drug effects ; Protein Structure, Tertiary/drug effects ; Structure-Activity Relationship
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    MR1 presents microbial vitamin B metabolites to MAIT cells (2012)
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    Publication Date: 2012-10-12
    Description: Antigen-presenting molecules, encoded by the major histocompatibility complex (MHC) and CD1 family, bind peptide- and lipid-based antigens, respectively, for recognition by T cells. Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like T cells in humans that are activated by an antigen(s) bound to the MHC class I-like molecule MR1. Although the identity of MR1-restricted antigen(s) is unknown, it is present in numerous bacteria and yeast. Here we show that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, we characterize related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, we show that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance. As many vitamin biosynthetic pathways are unique to bacteria and yeast, our data suggest that MAIT cells use these metabolites to detect microbial infection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kjer-Nielsen, Lars -- Patel, Onisha -- Corbett, Alexandra J -- Le Nours, Jerome -- Meehan, Bronwyn -- Liu, Ligong -- Bhati, Mugdha -- Chen, Zhenjun -- Kostenko, Lyudmila -- Reantragoon, Rangsima -- Williamson, Nicholas A -- Purcell, Anthony W -- Dudek, Nadine L -- McConville, Malcolm J -- O'Hair, Richard A J -- Khairallah, George N -- Godfrey, Dale I -- Fairlie, David P -- Rossjohn, Jamie -- McCluskey, James -- England -- Nature. 2012 Nov 29;491(7426):717-23. doi: 10.1038/nature11605. Epub 2012 Oct 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology & Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23051753" target="_blank"〉PubMed〈/a〉
    Keywords: Antigen Presentation ; Bacterial Infections/immunology/microbiology ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Folic Acid/chemistry/immunology/*metabolism ; Histocompatibility Antigens/chemistry/immunology ; Histocompatibility Antigens Class I/*chemistry/*immunology/metabolism ; Humans ; Immunologic Surveillance/immunology ; Jurkat Cells ; Ligands ; Lymphocyte Activation ; Models, Molecular ; Protein Refolding/drug effects ; Pterins/*chemistry/*immunology/metabolism/pharmacology ; Salmonella/immunology/metabolism ; Salmonella Infections/immunology/microbiology ; Static Electricity ; T-Lymphocytes/*immunology ; beta 2-Microglobulin/immunology/metabolism
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    Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction (2012)
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    Publication Date: 2012-11-09
    Description: Hearing and balance use hair cells in the inner ear to transform mechanical stimuli into electrical signals. Mechanical force from sound waves or head movements is conveyed to hair-cell transduction channels by tip links, fine filaments formed by two atypical cadherins known as protocadherin 15 and cadherin 23 (refs 4, 5). These two proteins are involved in inherited deafness and feature long extracellular domains that interact tip-to-tip in a Ca(2+)-dependent manner. However, the molecular architecture of this complex is unknown. Here we combine crystallography, molecular dynamics simulations and binding experiments to characterize the protocadherin 15-cadherin 23 bond. We find a unique cadherin interaction mechanism, in which the two most amino-terminal cadherin repeats (extracellular cadherin repeats 1 and 2) of each protein interact to form an overlapped, antiparallel heterodimer. Simulations predict that this tip-link bond is mechanically strong enough to resist forces in hair cells. In addition, the complex is shown to become unstable in response to Ca(2+) removal owing to increased flexure of Ca(2+)-free cadherin repeats. Finally, we use structures and biochemical measurements to study the molecular mechanisms by which deafness mutations disrupt tip-link function. Overall, our results shed light on the molecular mechanics of hair-cell sensory transduction and on new interaction mechanisms for cadherins, a large protein family implicated in tissue and organ morphogenesis, neural connectivity and cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518760/" 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/PMC3518760/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sotomayor, Marcos -- Weihofen, Wilhelm A -- Gaudet, Rachelle -- Corey, David P -- R01 DC002281/DC/NIDCD NIH HHS/ -- R01 DC02281/DC/NIDCD NIH HHS/ -- RC2GM093307/GM/NIGMS NIH HHS/ -- RR-15301/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 6;492(7427):128-32. doi: 10.1038/nature11590. Epub 2012 Nov 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23135401" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cadherins/*chemistry/genetics/*metabolism ; Calcium/metabolism/pharmacology ; Chromatography, Gel ; Crystallography, X-Ray ; Deafness/genetics ; Ear, Inner/cytology/*physiology ; Mechanotransduction, Cellular/*physiology ; Mice ; Models, Molecular ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Mutation/genetics ; Protein Binding/drug effects ; Protein Multimerization/drug effects ; Protein Precursors/*chemistry/genetics/*metabolism ; Repetitive Sequences, Amino Acid
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    The 2.8 A crystal structure of the dynein motor domain (2012)
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    Publication Date: 2012-03-09
    Description: Dyneins are microtubule-based AAA(+) motor complexes that power ciliary beating, cell division, cell migration and intracellular transport. Here we report the most complete structure obtained so far, to our knowledge, of the 380-kDa motor domain of Dictyostelium discoideum cytoplasmic dynein at 2.8 A resolution; the data are reliable enough to discuss the structure and mechanism at the level of individual amino acid residues. Features that can be clearly visualized at this resolution include the coordination of ADP in each of four distinct nucleotide-binding sites in the ring-shaped AAA(+) ATPase unit, a newly identified interaction interface between the ring and mechanical linker, and junctional structures between the ring and microtubule-binding stalk, all of which should be critical for the mechanism of dynein motility. We also identify a long-range allosteric communication pathway between the primary ATPase and the microtubule-binding sites. Our work provides a framework for understanding the mechanism of dynein-based motility.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kon, Takahide -- Oyama, Takuji -- Shimo-Kon, Rieko -- Imamula, Kenji -- Shima, Tomohiro -- Sutoh, Kazuo -- Kurisu, Genji -- England -- Nature. 2012 Mar 7;484(7394):345-50. doi: 10.1038/nature10955.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan. takahide.kon@protein.osaka-u.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22398446" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Diphosphate/metabolism ; Adenosine Triphosphate/metabolism ; Allosteric Regulation ; Binding Sites ; Crystallography, X-Ray ; Cytoplasmic Dyneins/*chemistry/metabolism ; Dictyostelium/*chemistry ; Hydrolysis ; Microtubules/metabolism ; Models, Biological ; Models, Molecular ; Movement ; Protein Structure, Tertiary ; Structure-Activity Relationship
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    Recognition of SUMO-modified PCNA requires tandem receptor motifs in Srs2 (2012)
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    Publication Date: 2012-03-03
    Description: Ubiquitin (Ub) and ubiquitin-like (Ubl) modifiers such as SUMO (also known as Smt3 in Saccharomyces cerevisiae) mediate signal transduction through post-translational modification of substrate proteins in pathways that control differentiation, apoptosis and the cell cycle, and responses to stress such as the DNA damage response. In yeast, the proliferating cell nuclear antigen PCNA (also known as Pol30) is modified by ubiquitin in response to DNA damage and by SUMO during S phase. Whereas Ub-PCNA can signal for recruitment of translesion DNA polymerases, SUMO-PCNA signals for recruitment of the anti-recombinogenic DNA helicase Srs2. It remains unclear how receptors such as Srs2 specifically recognize substrates after conjugation to Ub and Ubls. Here we show, through structural, biochemical and functional studies, that the Srs2 carboxy-terminal domain harbours tandem receptor motifs that interact independently with PCNA and SUMO and that both motifs are required to recognize SUMO-PCNA specifically. The mechanism presented is pertinent to understanding how other receptors specifically recognize Ub- and Ubl-modified substrates to facilitate signal transduction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306252/" 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/PMC3306252/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Armstrong, Anthony A -- Mohideen, Firaz -- Lima, Christopher D -- F32 GM086066/GM/NIGMS NIH HHS/ -- F32 GM086066-01/GM/NIGMS NIH HHS/ -- F32 GM086066-02/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- P41RR012408/RR/NCRR NIH HHS/ -- R01 GM065872/GM/NIGMS NIH HHS/ -- R01 GM065872-08/GM/NIGMS NIH HHS/ -- R01 GM065872-09/GM/NIGMS NIH HHS/ -- R01 GM065872-10/GM/NIGMS NIH HHS/ -- R01 GM065872-11/GM/NIGMS NIH HHS/ -- R01 GM065872-12/GM/NIGMS NIH HHS/ -- RR-15301/RR/NCRR NIH HHS/ -- England -- Nature. 2012 Feb 29;483(7387):59-63. doi: 10.1038/nature10883.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22382979" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Antigens, Nuclear/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; DNA Helicases/*chemistry/*metabolism ; Methylation ; Models, Molecular ; Proliferating Cell Nuclear Antigen/chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*chemistry/genetics/growth & development ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism ; Small Ubiquitin-Related Modifier Proteins/chemistry/*metabolism ; Structure-Activity Relationship ; *Sumoylation
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    Structure of the agonist-bound neurotensin receptor (2012)
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    Publication Date: 2012-10-12
    Description: Neurotensin (NTS) is a 13-amino-acid peptide that functions as both a neurotransmitter and a hormone through the activation of the neurotensin receptor NTSR1, a G-protein-coupled receptor (GPCR). In the brain, NTS modulates the activity of dopaminergic systems, opioid-independent analgesia, and the inhibition of food intake; in the gut, NTS regulates a range of digestive processes. Here we present the structure at 2.8 A resolution of Rattus norvegicus NTSR1 in an active-like state, bound to NTS(8-13), the carboxy-terminal portion of NTS responsible for agonist-induced activation of the receptor. The peptide agonist binds to NTSR1 in an extended conformation nearly perpendicular to the membrane plane, with the C terminus oriented towards the receptor core. Our findings provide, to our knowledge, the first insight into the binding mode of a peptide agonist to a GPCR and may support the development of non-peptide ligands that could be useful in the treatment of neurological disorders, cancer and obesity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482300/" 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/PMC3482300/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉White, Jim F -- Noinaj, Nicholas -- Shibata, Yoko -- Love, James -- Kloss, Brian -- Xu, Feng -- Gvozdenovic-Jeremic, Jelena -- Shah, Priyanka -- Shiloach, Joseph -- Tate, Christopher G -- Grisshammer, Reinhard -- MC_U105197215/Medical Research Council/United Kingdom -- P50 GM073197/GM/NIGMS NIH HHS/ -- U105197215/Medical Research Council/United Kingdom -- U54GM075026/GM/NIGMS NIH HHS/ -- ZIA NS003016-05/Intramural NIH HHS/ -- England -- Nature. 2012 Oct 25;490(7421):508-13. doi: 10.1038/nature11558. Epub 2012 Oct 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Membrane Protein Structure Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services, Rockville, Maryland 20852, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23051748" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Animals ; Bacteriophage T4 ; Binding Sites ; Crystallography, X-Ray ; Models, Molecular ; Muramidase ; Mutation ; Neurotensin/chemistry/genetics/*metabolism ; Protein Conformation ; Rats ; Receptors, Neurotensin/*agonists/*chemistry/genetics/metabolism
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    Molecular mechanism of ATP binding and ion channel activation in P2X receptors (2012)
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    Publication Date: 2012-04-27
    Description: P2X receptors are trimeric ATP-activated ion channels permeable to Na+, K+ and Ca2+. The seven P2X receptor subtypes are implicated in physiological processes that include modulation of synaptic transmission, contraction of smooth muscle, secretion of chemical transmitters and regulation of immune responses. Despite the importance of P2X receptors in cellular physiology, the three-dimensional composition of the ATP-binding site, the structural mechanism of ATP-dependent ion channel gating and the architecture of the open ion channel pore are unknown. Here we report the crystal structure of the zebrafish P2X4 receptor in complex with ATP and a new structure of the apo receptor. The agonist-bound structure reveals a previously unseen ATP-binding motif and an open ion channel pore. ATP binding induces cleft closure of the nucleotide-binding pocket, flexing of the lower body beta-sheet and a radial expansion of the extracellular vestibule. The structural widening of the extracellular vestibule is directly coupled to the opening of the ion channel pore by way of an iris-like expansion of the transmembrane helices. The structural delineation of the ATP-binding site and the ion channel pore, together with the conformational changes associated with ion channel gating, will stimulate development of new pharmacological agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391165/" 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/PMC3391165/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hattori, Motoyuki -- Gouaux, Eric -- P30 NS061800/NS/NINDS NIH HHS/ -- R01 GM100400/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 10;485(7397):207-12. doi: 10.1038/nature11010.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22535247" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/chemistry/*metabolism ; Amino Acid Motifs ; Animals ; Apoproteins/chemistry/metabolism ; Binding Sites ; Crystallization ; Crystallography, X-Ray ; *Ion Channel Gating ; Models, Molecular ; Receptors, Purinergic P2X4/*chemistry/*metabolism ; Structure-Activity Relationship ; Zebrafish
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    Structure of the mitotic checkpoint complex (2012)
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    Publication Date: 2012-03-23
    Description: In mitosis, the spindle assembly checkpoint (SAC) ensures genome stability by delaying chromosome segregation until all sister chromatids have achieved bipolar attachment to the mitotic spindle. The SAC is imposed by the mitotic checkpoint complex (MCC), whose assembly is catalysed by unattached chromosomes and which binds and inhibits the anaphase-promoting complex/cyclosome (APC/C), the E3 ubiquitin ligase that initiates chromosome segregation. Here, using the crystal structure of Schizosaccharomyces pombe MCC (a complex of mitotic spindle assembly checkpoint proteins Mad2, Mad3 and APC/C co-activator protein Cdc20), we reveal the molecular basis of MCC-mediated APC/C inhibition and the regulation of MCC assembly. The MCC inhibits the APC/C by obstructing degron recognition sites on Cdc20 (the substrate recruitment subunit of the APC/C) and displacing Cdc20 to disrupt formation of a bipartite D-box receptor with the APC/C subunit Apc10. Mad2, in the closed conformation (C-Mad2), stabilizes the complex by optimally positioning the Mad3 KEN-box degron to bind Cdc20. Mad3 and p31(comet) (also known as MAD2L1-binding protein) compete for the same C-Mad2 interface, which explains how p31(comet) disrupts MCC assembly to antagonize the SAC. This study shows how APC/C inhibition is coupled to degron recognition by co-activators.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chao, William C H -- Kulkarni, Kiran -- Zhang, Ziguo -- Kong, Eric H -- Barford, David -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Mar 21;484(7393):208-13. doi: 10.1038/nature10896.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, SW3 6JB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22437499" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Anaphase-Promoting Complex-Cyclosome ; Cdc20 Proteins ; Cdh1 Proteins ; Cell Cycle Proteins/*chemistry/metabolism ; Conserved Sequence ; Crystallography, X-Ray ; Humans ; *M Phase Cell Cycle Checkpoints ; Mad2 Proteins ; Models, Molecular ; Multiprotein Complexes/*chemistry/metabolism ; Nuclear Proteins/*chemistry/metabolism ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism ; Schizosaccharomyces/*chemistry ; Schizosaccharomyces pombe Proteins/*chemistry/metabolism ; Spindle Apparatus ; Structure-Activity Relationship ; Substrate Specificity ; Ubiquitin-Protein Ligase Complexes/antagonists & ; inhibitors/chemistry/metabolism/ultrastructure
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    Structure of the Mediator head module (2012)
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    Publication Date: 2012-11-06
    Description: Gene transcription by RNA polymerase (Pol) II requires the coactivator complex Mediator. Mediator connects transcriptional regulators and Pol II, and is linked to human disease. Mediator from the yeast Saccharomyces cerevisiae has a molecular mass of 1.4 megadaltons and comprises 25 subunits that form the head, middle, tail and kinase modules. The head module constitutes one-half of the essential Mediator core, and comprises the conserved subunits Med6, Med8, Med11, Med17, Med18, Med20 and Med22. Recent X-ray analysis of the S. cerevisiae head module at 4.3 A resolution led to a partial architectural model with three submodules called neck, fixed jaw and moveable jaw. Here we determine de novo the crystal structure of the head module from the fission yeast Schizosaccharomyces pombe at 3.4 A resolution. Structure solution was enabled by new structures of Med6 and the fixed jaw, and previous structures of the moveable jaw and part of the neck, and required deletion of Med20. The S. pombe head module resembles the head of a crocodile with eight distinct elements, of which at least four are mobile. The fixed jaw comprises tooth and nose domains, whereas the neck submodule contains a helical spine and one limb, with shoulder, arm and finger elements. The arm and the essential shoulder contact other parts of Mediator. The jaws and a central joint are implicated in interactions with Pol II and its carboxy-terminal domain, and the joint is required for transcription in vitro. The S. pombe head module structure leads to a revised model of the S. cerevisiae module, reveals a high conservation and flexibility, explains known mutations, and provides the basis for unravelling a central mechanism of gene regulation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lariviere, Laurent -- Plaschka, Clemens -- Seizl, Martin -- Wenzeck, Larissa -- Kurth, Fabian -- Cramer, Patrick -- England -- Nature. 2012 Dec 20;492(7429):448-51. doi: 10.1038/nature11670. Epub 2012 Oct 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Center and Department of Biochemistry, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universitat Munchen, Feodor-Lynen-Strasse 25, 81377 Munich, Germany. larivier@genzentrum.lmu.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23123849" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; DNA Polymerase II/metabolism ; Mediator Complex/*chemistry/metabolism ; Models, Molecular ; Pliability ; Protein Structure, Tertiary ; Protein Subunits/*chemistry/metabolism ; RNA Polymerase II/chemistry/metabolism ; Saccharomyces cerevisiae/*chemistry/genetics ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism ; Schizosaccharomyces/chemistry ; Structural Homology, Protein
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    Structure and function of Zucchini endoribonuclease in piRNA biogenesis (2012)
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    Publication Date: 2012-10-16
    Description: PIWI-interacting RNAs (piRNAs) silence transposons to maintain genome integrity in animal germ lines. piRNAs are classified as primary and secondary piRNAs, depending on their biogenesis machinery. Primary piRNAs are processed from long non-coding RNA precursors transcribed from piRNA clusters in the genome through the primary processing pathway. Although the existence of a ribonuclease participating in this pathway has been predicted, its molecular identity remained unknown. Here we show that Zucchini (Zuc), a mitochondrial phospholipase D (PLD) superfamily member, is an endoribonuclease essential for primary piRNA biogenesis. We solved the crystal structure of Drosophila melanogaster Zuc (DmZuc) at 1.75 A resolution. The structure revealed that DmZuc has a positively charged, narrow catalytic groove at the dimer interface, which could accommodate a single-stranded, but not a double-stranded, RNA. DmZuc and the mouse homologue MmZuc (also known as Pld6 and MitoPLD) showed endoribonuclease activity for single-stranded RNAs in vitro. The RNA cleavage products bear a 5'-monophosphate group, a hallmark of mature piRNAs. Mutational analyses revealed that the conserved active-site residues of DmZuc are critical for the ribonuclease activity in vitro, and for piRNA maturation and transposon silencing in vivo. We propose a model for piRNA biogenesis in animal germ lines, in which the Zuc endoribonuclease has a key role in primary piRNA maturation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nishimasu, Hiroshi -- Ishizu, Hirotsugu -- Saito, Kuniaki -- Fukuhara, Satoshi -- Kamatani, Miharu K -- Bonnefond, Luc -- Matsumoto, Naoki -- Nishizawa, Tomohiro -- Nakanaga, Keita -- Aoki, Junken -- Ishitani, Ryuichiro -- Siomi, Haruhiko -- Siomi, Mikiko C -- Nureki, Osamu -- England -- Nature. 2012 Nov 8;491(7423):284-7. doi: 10.1038/nature11509. Epub 2012 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23064230" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; DNA Transposable Elements/genetics ; Drosophila Proteins/*chemistry/*metabolism ; Drosophila melanogaster/*enzymology/genetics ; Endoribonucleases/*chemistry/*metabolism ; Gene Silencing ; Models, Molecular ; Molecular Sequence Data ; Protein Conformation ; RNA, Small Interfering/biosynthesis/chemistry/genetics/*metabolism ; Structure-Activity Relationship
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    Alternating-access mechanism in conformationally asymmetric trimers of the betaine transporter BetP (2012)
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    Publication Date: 2012-09-04
    Description: Betaine and Na(+) symport has been extensively studied in the osmotically regulated transporter BetP from Corynebacterium glutamicum, a member of the betaine/choline/carnitine transporter family, which shares the conserved LeuT-like fold of two inverted structural repeats. BetP adjusts its transport activity by sensing the cytoplasmic K(+) concentration as a measure for hyperosmotic stress via the osmosensing carboxy-terminal domain. BetP needs to be in a trimeric state for communication between individual protomers through several intratrimeric interaction sites. Recently, crystal structures of inward-facing BetP trimers have contributed to our understanding of activity regulation on a molecular level. Here we report new crystal structures, which reveal two conformationally asymmetric BetP trimers, capturing among them three distinct transport states. We observe a total of four new conformations at once: an outward-open apo and an outward-occluded apo state, and two closed transition states--one in complex with betaine and one substrate-free. On the basis of these new structures, we identified local and global conformational changes in BetP that underlie the molecular transport mechanism, which partially resemble structural changes observed in other sodium-coupled LeuT-like fold transporters, but show differences we attribute to the osmolytic nature of betaine, the exclusive substrate specificity and the regulatory properties of BetP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perez, Camilo -- Koshy, Caroline -- Yildiz, Ozkan -- Ziegler, Christine -- England -- Nature. 2012 Oct 4;490(7418):126-30. doi: 10.1038/nature11403. Epub 2012 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max-Planck Institute of Biophysics, Department of Structural Biology, D-60438 Frankfurt am Main, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22940865" target="_blank"〉PubMed〈/a〉
    Keywords: Apoproteins/chemistry/metabolism ; Bacterial Proteins/*chemistry/*metabolism ; Betaine/chemistry/*metabolism ; Binding Sites ; Biological Transport ; Carrier Proteins/*chemistry/*metabolism ; Corynebacterium glutamicum/*chemistry ; Crystallography, X-Ray ; Cytoplasm/metabolism ; Models, Molecular ; Periplasm/metabolism ; Plasma Membrane Neurotransmitter Transport Proteins/chemistry ; Protein Conformation ; Protein Folding ; *Protein Multimerization ; Sodium/metabolism ; Structure-Activity Relationship
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    A new understanding of the decoding principle on the ribosome (2012)
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    Publication Date: 2012-03-23
    Description: During protein synthesis, the ribosome accurately selects transfer RNAs (tRNAs) in accordance with the messenger RNA (mRNA) triplet in the decoding centre. tRNA selection is initiated by elongation factor Tu, which delivers tRNA to the aminoacyl tRNA-binding site (A site) and hydrolyses GTP upon establishing codon-anticodon interactions in the decoding centre. At the following proofreading step the ribosome re-examines the tRNA and rejects it if it does not match the A codon. It was suggested that universally conserved G530, A1492 and A1493 of 16S ribosomal RNA, critical for tRNA binding in the A site, actively monitor cognate tRNA, and that recognition of the correct codon-anticodon duplex induces an overall ribosome conformational change (domain closure). Here we propose an integrated mechanism for decoding based on six X-ray structures of the 70S ribosome determined at 3.1-3.4 A resolution, modelling cognate or near-cognate states of the decoding centre at the proofreading step. We show that the 30S subunit undergoes an identical domain closure upon binding of either cognate or near-cognate tRNA. This conformational change of the 30S subunit forms a decoding centre that constrains the mRNA in such a way that the first two nucleotides of the A codon are limited to form Watson-Crick base pairs. When U.G and G.U mismatches, generally considered to form wobble base pairs, are at the first or second codon-anticodon position, the decoding centre forces this pair to adopt the geometry close to that of a canonical C.G pair. This by itself, or with distortions in the codon-anticodon mini-helix and the anticodon loop, causes the near-cognate tRNA to dissociate from the ribosome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Demeshkina, Natalia -- Jenner, Lasse -- Westhof, Eric -- Yusupov, Marat -- Yusupova, Gulnara -- 294312/European Research Council/International -- England -- Nature. 2012 Mar 21;484(7393):256-9. doi: 10.1038/nature10913.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departement de Biologie et de Genomique Structurales, Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch 67400, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22437501" target="_blank"〉PubMed〈/a〉
    Keywords: Anticodon/genetics/metabolism ; Base Pairing ; Base Sequence ; Codon/genetics/metabolism ; Crystallography, X-Ray ; *Models, Biological ; Models, Genetic ; Models, Molecular ; Nucleic Acid Conformation ; Protein Biosynthesis ; Protein Conformation ; RNA, Messenger/genetics/metabolism ; RNA, Ribosomal, 23S/genetics/metabolism ; RNA, Transfer, Amino Acid-Specific/chemistry/genetics/metabolism ; Ribosomes/*chemistry/genetics/*metabolism ; Thermus thermophilus
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    Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001 (2012)
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    Publication Date: 2012-01-24
    Description: Cytochrome P450 17A1 (also known as CYP17A1 and cytochrome P450c17) catalyses the biosynthesis of androgens in humans. As prostate cancer cells proliferate in response to androgen steroids, CYP17A1 inhibition is a new strategy to prevent androgen synthesis and treat lethal metastatic castration-resistant prostate cancer, but drug development has been hampered by lack of information regarding the structure of CYP17A1. Here we report X-ray crystal structures of CYP17A1, which were obtained in the presence of either abiraterone, a first-in-class steroidal inhibitor recently approved by the US Food and Drug Administration for late-stage prostate cancer, or TOK-001, an inhibitor that is currently undergoing clinical trials. Both of these inhibitors bind the haem iron, forming a 60 degrees angle above the haem plane and packing against the central I helix with the 3beta-OH interacting with aspargine 202 in the F helix. Notably, this binding mode differs substantially from those that are predicted by homology models and from steroids in other cytochrome P450 enzymes with known structures, and some features of this binding mode are more similar to steroid receptors. Whereas the overall structure of CYP17A1 provides a rationale for understanding many mutations that are found in patients with steroidogenic diseases, the active site reveals multiple steric and hydrogen bonding features that will facilitate a better understanding of the enzyme's dual hydroxylase and lyase catalytic capabilities and assist in rational drug design. Specifically, structure-based design is expected to aid development of inhibitors that bind only CYP17A1 and solely inhibit its androgen-generating lyase activity to improve treatment of prostate and other hormone-responsive cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271139/" 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/PMC3271139/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeVore, Natasha M -- Scott, Emily E -- GM076343/GM/NIGMS NIH HHS/ -- P20 RR017708/RR/NCRR NIH HHS/ -- P20 RR017708-09/RR/NCRR NIH HHS/ -- R01 GM076343/GM/NIGMS NIH HHS/ -- R01 GM076343-06/GM/NIGMS NIH HHS/ -- RR030926/RR/NCRR NIH HHS/ -- RR17708/RR/NCRR NIH HHS/ -- England -- Nature. 2012 Jan 22;482(7383):116-9. doi: 10.1038/nature10743.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, University of Kansas, Lawrence, Kansas 66045, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22266943" target="_blank"〉PubMed〈/a〉
    Keywords: Androstadienes/*chemistry/metabolism ; Androstenes ; Androstenols/*chemistry/metabolism ; Antineoplastic Agents/*chemistry/metabolism ; Benzimidazoles/*chemistry/metabolism ; Biocatalysis/drug effects ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Hydrogen Bonding ; Ligands ; Male ; Models, Molecular ; *Prostatic Neoplasms/drug therapy ; Protein Conformation ; Receptors, Androgen/chemistry/metabolism ; Steroid 17-alpha-Hydroxylase/*antagonists & inhibitors/*chemistry/metabolism ; United States ; United States Food and Drug Administration
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    Accelerated disassembly of IgE-receptor complexes by a disruptive macromolecular inhibitor (2012)
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    Publication Date: 2012-10-30
    Description: IgE antibodies bind the high-affinity IgE Fc receptor (FcepsilonRI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response. Inhibitors of IgE-FcepsilonRI binding have been identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma. However, preformed IgE-FcepsilonRI complexes that prime cells before allergen exposure dissociate extremely slowly and cannot be disrupted by strictly competitive inhibitors. IgE-Fc conformational flexibility indicated that inhibition could be mediated by allosteric or other non-classical mechanisms. Here we demonstrate that an engineered protein inhibitor, DARPin E2_79 (refs 9, 10, 11), acts through a non-classical inhibition mechanism, not only blocking IgE-FcepsilonRI interactions, but actively stimulating the dissociation of preformed ligand-receptor complexes. The structure of the E2_79-IgE-Fc(3-4) complex predicts the presence of two non-equivalent E2_79 sites in the asymmetric IgE-FcepsilonRI complex, with site 1 distant from the receptor and site 2 exhibiting partial steric overlap. Although the structure is indicative of an allosteric inhibition mechanism, mutational studies and quantitative kinetic modelling indicate that E2_79 acts through a facilitated dissociation mechanism at site 2 alone. These results demonstrate that high-affinity IgE-FcepsilonRI complexes can be actively dissociated to block the allergic response and suggest that protein-protein complexes may be more generally amenable to active disruption by macromolecular inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504642/" 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/PMC3504642/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Beomkyu -- Eggel, Alexander -- Tarchevskaya, Svetlana S -- Vogel, Monique -- Prinz, Heino -- Jardetzky, Theodore S -- AI-18939/AI/NIAID NIH HHS/ -- R21 NS074067/NS/NINDS NIH HHS/ -- R37 AI038972/AI/NIAID NIH HHS/ -- England -- Nature. 2012 Nov 22;491(7425):613-7. doi: 10.1038/nature11546. Epub 2012 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23103871" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Ankyrin Repeat ; Binding Sites/drug effects ; Crystallography, X-Ray ; Fluorescence ; Immunoglobulin E/chemistry/immunology/*metabolism ; Kinetics ; Ligands ; Models, Molecular ; Mutant Proteins/chemistry/genetics/metabolism/pharmacology ; Mutation ; Protein Binding/drug effects ; Protein Structure, Tertiary ; Receptors, IgE/*antagonists & inhibitors/chemistry/immunology/*metabolism ; Recombinant Fusion Proteins/chemistry/genetics/metabolism/*pharmacology ; Surface Plasmon Resonance
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    Structure of a presenilin family intramembrane aspartate protease (2012)
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    Publication Date: 2012-12-21
    Description: Presenilin and signal peptide peptidase (SPP) are intramembrane aspartyl proteases that regulate important biological functions in eukaryotes. Mechanistic understanding of presenilin and SPP has been hampered by lack of relevant structural information. Here we report the crystal structure of a presenilin/SPP homologue (PSH) from the archaeon Methanoculleus marisnigri JR1. The protease, comprising nine transmembrane segments (TMs), adopts a previously unreported protein fold. The amino-terminal domain, consisting of TM1-6, forms a horseshoe-shaped structure, surrounding TM7-9 of the carboxy-terminal domain. The two catalytic aspartate residues are located on the cytoplasmic side of TM6 and TM7, spatially close to each other and approximately 8 A into the lipid membrane surface. Water molecules gain constant access to the catalytic aspartates through a large cavity between the amino- and carboxy-terminal domains. Structural analysis reveals insights into the presenilin/SPP family of intramembrane proteases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Xiaochun -- Dang, Shangyu -- Yan, Chuangye -- Gong, Xinqi -- Wang, Jiawei -- Shi, Yigong -- England -- Nature. 2013 Jan 3;493(7430):56-61. doi: 10.1038/nature11801. Epub 2012 Dec 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ministry of Education Key Laboratory of Protein Science, 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/23254940" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Aspartic Acid Endopeptidases/*chemistry ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Methanomicrobiaceae/*enzymology ; Models, Molecular ; Molecular Sequence Data ; Presenilin-1/chemistry ; Presenilins/*chemistry ; Protein Multimerization ; Protein Structure, Quaternary ; Structural Homology, Protein
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    ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase (2012)
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    Publication Date: 2012-12-25
    Description: Febrifugine is the active component of the Chinese herb Chang Shan (Dichroa febrifuga Lour.), which has been used for treating malaria-induced fever for about 2,000 years. Halofuginone (HF), the halogenated derivative of febrifugine, has been tested in clinical trials for potential therapeutic applications in cancer and fibrotic disease. Recently, HF was reported to inhibit T(H)17 cell differentiation by activating the amino acid response pathway, through inhibiting human prolyl-transfer RNA synthetase (ProRS) to cause intracellular accumulation of uncharged tRNA. Curiously, inhibition requires the presence of unhydrolysed ATP. Here we report an unusual 2.0 A structure showing that ATP directly locks onto and orients two parts of HF onto human ProRS, so that one part of HF mimics bound proline and the other mimics the 3' end of bound tRNA. Thus, HF is a new type of ATP-dependent inhibitor that simultaneously occupies two different substrate binding sites on ProRS. Moreover, our structure indicates a possible similar mechanism of action for febrifugine in malaria treatment. Finally, the elucidation here of a two-site modular targeting activity of HF raises the possibility that substrate-directed capture of similar inhibitors might be a general mechanism that could be applied to other synthetases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569068/" 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/PMC3569068/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Huihao -- Sun, Litao -- Yang, Xiang-Lei -- Schimmel, Paul -- GM15539/GM/NIGMS NIH HHS/ -- GM23562/GM/NIGMS NIH HHS/ -- GM88278/GM/NIGMS NIH HHS/ -- R01 GM088278/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Feb 7;494(7435):121-4. doi: 10.1038/nature11774. Epub 2012 Dec 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Skaggs Institute for Chemical Biology, Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23263184" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/chemistry/*metabolism/pharmacology ; Amino Acyl-tRNA Synthetases/antagonists & inhibitors/*chemistry/*metabolism ; Antimalarials/chemistry/pharmacology ; Binding Sites ; Crystallography, X-Ray ; Herbal Medicine ; Humans ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions ; Ligands ; Medicine, Chinese Traditional ; Models, Molecular ; Piperidines/*chemistry/*metabolism/pharmacology ; Proline/chemistry/metabolism ; Quinazolines/chemistry/pharmacology ; Quinazolinones/*chemistry/*metabolism/pharmacology ; RNA, Transfer/chemistry/metabolism
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    Cross-neutralization of influenza A viruses mediated by a single antibody loop (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-09-18
    Description: Immune recognition of protein antigens relies on the combined interaction of multiple antibody loops, which provide a fairly large footprint and constrain the size and shape of protein surfaces that can be targeted. Single protein loops can mediate extremely high-affinity binding, but it is unclear whether such a mechanism is available to antibodies. Here we report the isolation and characterization of an antibody called C05, which neutralizes strains from multiple subtypes of influenza A virus, including H1, H2 and H3. X-ray and electron microscopy structures show that C05 recognizes conserved elements of the receptor-binding site on the haemagglutinin surface glycoprotein. Recognition of the haemagglutinin receptor-binding site is dominated by a single heavy-chain complementarity-determining region 3 loop, with minor contacts from heavy-chain complementarity-determining region 1, and is sufficient to achieve nanomolar binding with a minimal footprint. Thus, binding predominantly with a single loop can allow antibodies to target small, conserved functional sites on otherwise hypervariable antigens.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538848/" 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/PMC3538848/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ekiert, Damian C -- Kashyap, Arun K -- Steel, John -- Rubrum, Adam -- Bhabha, Gira -- Khayat, Reza -- Lee, Jeong Hyun -- Dillon, Michael A -- O'Neil, Ryann E -- Faynboym, Aleksandr M -- Horowitz, Michael -- Horowitz, Lawrence -- Ward, Andrew B -- Palese, Peter -- Webby, Richard -- Lerner, Richard A -- Bhatt, Ramesh R -- Wilson, Ian A -- GM080209/GM/NIGMS NIH HHS/ -- HHSN266200700010C/PHS HHS/ -- P01 AI058113/AI/NIAID NIH HHS/ -- P01AI058113/AI/NIAID NIH HHS/ -- P41 RR017573/RR/NCRR NIH HHS/ -- T32 GM080209/GM/NIGMS NIH HHS/ -- U01 AI070373/AI/NIAID NIH HHS/ -- U01AI070373/AI/NIAID NIH HHS/ -- U54 GM094586/GM/NIGMS NIH HHS/ -- U54-AI057158/AI/NIAID NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Sep 27;489(7417):526-32. doi: 10.1038/nature11414. Epub 2012 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22982990" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Neutralizing/*chemistry/genetics/*immunology ; Antibodies, Viral/*chemistry/genetics/*immunology ; Antibody Specificity/genetics/*immunology ; Antigens, Viral/chemistry/immunology ; Binding Sites ; Complementarity Determining Regions/chemistry/genetics/immunology ; Conserved Sequence ; Cross Reactions/genetics/immunology ; Crystallography, X-Ray ; Enzyme-Linked Immunosorbent Assay ; Epitopes/chemistry/immunology ; Hemagglutinin Glycoproteins, Influenza Virus/chemistry/immunology ; Influenza A Virus, H1N1 Subtype/chemistry/immunology ; Influenza A Virus, H3N2 Subtype/chemistry/immunology ; Influenza A virus/chemistry/*classification/*immunology ; Influenza Vaccines/immunology ; Mice ; Models, Molecular ; Molecular Sequence Data ; Mutation/genetics ; Orthomyxoviridae Infections/immunology/prevention & control/virology ; Protein Conformation
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    The molecular basis of phosphate discrimination in arsenate-rich environments (2012)
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    Publication Date: 2012-10-05
    Description: Arsenate and phosphate are abundant on Earth and have striking similarities: nearly identical pK(a) values, similarly charged oxygen atoms, and thermochemical radii that differ by only 4% (ref. 3). Phosphate is indispensable and arsenate is toxic, but this extensive similarity raises the question whether arsenate may substitute for phosphate in certain niches. However, whether it is used or excluded, discriminating phosphate from arsenate is a paramount challenge. Enzymes that utilize phosphate, for example, have the same binding mode and kinetic parameters as arsenate, and the latter's presence therefore decouples metabolism. Can proteins discriminate between these two anions, and how would they do so? In particular, cellular phosphate uptake systems face a challenge in arsenate-rich environments. Here we describe a molecular mechanism for this process. We examined the periplasmic phosphate-binding proteins (PBPs) of the ABC-type transport system that mediates phosphate uptake into bacterial cells, including two PBPs from the arsenate-rich Mono Lake Halomonas strain GFAJ-1. All PBPs tested are capable of discriminating phosphate over arsenate at least 500-fold. The exception is one of the PBPs of GFAJ-1 that shows roughly 4,500-fold discrimination and its gene is highly expressed under phosphate-limiting conditions. Sub-angstrom-resolution structures of Pseudomonas fluorescens PBP with both arsenate and phosphate show a unique mode of binding that mediates discrimination. An extensive network of dipole-anion interactions, and of repulsive interactions, results in the 4% larger arsenate distorting a unique low-barrier hydrogen bond. These features enable the phosphate transport system to bind phosphate selectively over arsenate (at least 10(3) excess) even in highly arsenate-rich environments.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elias, Mikael -- Wellner, Alon -- Goldin-Azulay, Korina -- Chabriere, Eric -- Vorholt, Julia A -- Erb, Tobias J -- Tawfik, Dan S -- England -- Nature. 2012 Nov 1;491(7422):134-7. doi: 10.1038/nature11517. Epub 2012 Oct 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. mikael.elias@weizmann.ac.il〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23034649" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Arsenates/*chemistry/*metabolism ; Binding Sites ; Biological Transport ; Crystallography, X-Ray ; Drug Resistance, Bacterial ; Ecosystem ; Escherichia coli/chemistry ; Hydrogen Bonding ; Lakes/microbiology ; Models, Molecular ; Periplasmic Binding Proteins/chemistry/genetics/metabolism ; Phosphate-Binding Proteins/*chemistry/genetics/*metabolism ; Phosphates/*chemistry/*metabolism ; Pseudomonas fluorescens/*chemistry ; Substrate Specificity
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    DAXX envelops a histone H3.3-H4 dimer for H3.3-specific recognition (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-19
    Description: Histone chaperones represent a structurally and functionally diverse family of histone-binding proteins that prevent promiscuous interactions of histones before their assembly into chromatin. DAXX is a metazoan histone chaperone specific to the evolutionarily conserved histone variant H3.3. Here we report the crystal structures of the DAXX histone-binding domain with a histone H3.3-H4 dimer, including mutants within DAXX and H3.3, together with in vitro and in vivo functional studies that elucidate the principles underlying H3.3 recognition specificity. Occupying 40% of the histone surface-accessible area, DAXX wraps around the H3.3-H4 dimer, with complex formation accompanied by structural transitions in the H3.3-H4 histone fold. DAXX uses an extended alpha-helical conformation to compete with major inter-histone, DNA and ASF1 interaction sites. Our structural studies identify recognition elements that read out H3.3-specific residues, and functional studies address the contributions of Gly 90 in H3.3 and Glu 225 in DAXX to chaperone-mediated H3.3 variant recognition specificity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056191/" 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/PMC4056191/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elsasser, Simon J -- Huang, Hongda -- Lewis, Peter W -- Chin, Jason W -- Allis, C David -- Patel, Dinshaw J -- 1S10RR022321-01/RR/NCRR NIH HHS/ -- 1S10RR027037-01/RR/NCRR NIH HHS/ -- MC_U105181009/Medical Research Council/United Kingdom -- P30 EB009998/EB/NIBIB NIH HHS/ -- P30-EB-009998/EB/NIBIB NIH HHS/ -- S10 RR022321/RR/NCRR NIH HHS/ -- S10 RR027037/RR/NCRR NIH HHS/ -- U105181009/PHS HHS/ -- UD99999908/PHS HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2012 Nov 22;491(7425):560-5. doi: 10.1038/nature11608. Epub 2012 Oct 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23075851" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/chemistry/metabolism ; Amino Acid Sequence ; Binding, Competitive ; Cell Cycle Proteins/genetics/metabolism ; Crystallography, X-Ray ; DNA/chemistry/*metabolism ; Histone Chaperones/chemistry/metabolism ; Histones/*chemistry/*metabolism ; Humans ; Models, Molecular ; Molecular Sequence Data ; Nuclear Proteins/chemistry/metabolism ; Nucleosomes/chemistry/metabolism ; Protein Conformation ; Protein Multimerization ; Substrate Specificity ; Water/chemistry/metabolism
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    Structure and dynamics of the M3 muscarinic acetylcholine receptor (2012)
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    Publication Date: 2012-02-24
    Description: Acetylcholine, the first neurotransmitter to be identified, exerts many of its physiological actions via activation of a family of G-protein-coupled receptors (GPCRs) known as muscarinic acetylcholine receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G-protein coupling preference and the physiological responses they mediate. Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences. We describe here the structure of the G(q/11)-coupled M3 mAChR ('M3 receptor', from rat) bound to the bronchodilator drug tiotropium and identify the binding mode for this clinically important drug. This structure, together with that of the G(i/o)-coupled M2 receptor, offers possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows a structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and provide additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529910/" 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/PMC3529910/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kruse, Andrew C -- Hu, Jianxin -- Pan, Albert C -- Arlow, Daniel H -- Rosenbaum, Daniel M -- Rosemond, Erica -- Green, Hillary F -- Liu, Tong -- Chae, Pil Seok -- Dror, Ron O -- Shaw, David E -- Weis, William I -- Wess, Jurgen -- Kobilka, Brian K -- GM56169/GM/NIGMS NIH HHS/ -- NS028471/NS/NINDS NIH HHS/ -- R01 GM083118/GM/NIGMS NIH HHS/ -- R01 NS028471/NS/NINDS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2012 Feb 22;482(7386):552-6. doi: 10.1038/nature10867.〈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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22358844" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylcholine/chemistry/metabolism ; Allosteric Site ; Animals ; COS Cells ; Crystallization ; Crystallography, X-Ray ; Kinetics ; Ligands ; Models, Molecular ; Molecular Dynamics Simulation ; Radioligand Assay ; Rats ; Receptor, Muscarinic M3/*chemistry/*metabolism ; Scopolamine Derivatives/chemistry/metabolism ; Substrate Specificity ; Tiotropium Bromide
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    Structure of AMP-PNP-bound vitamin B12 transporter BtuCD-F (2012)
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    Publication Date: 2012-09-25
    Description: The ATP-binding cassette (ABC) transporter BtuCD mediates the uptake of vitamin B(12) across the inner membrane of Escherichia coli. Previous structures have shown the conformations of apo states, but the transport mechanism has remained unclear. Here we report the 3.5 A crystal structure of the transporter-binding protein complex BtuCD-BtuF (BtuCD-F) trapped in an beta-gamma-imidoadenosine 5'-phosphate (AMP-PNP)-bound intermediate state. Although the ABC domains (BtuD subunits) form the expected closed sandwich dimer, the membrane-spanning BtuC subunits adopt a new conformation, with the central translocation pathway sealed by a previously unrecognized cytoplasmic gate. A fully enclosed cavity is thus formed approximately halfway across the membrane. It is large enough to accommodate a vitamin B(12) molecule, and radioligand trapping showed that liposome-reconstituted BtuCD-F indeed contains bound B(12) in the presence of AMP-PNP. In combination with engineered disulphide crosslinking and functional assays, our data suggest an unexpected peristaltic transport mechanism that is distinct from those observed in other ABC transporters.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Korkhov, Vladimir M -- Mireku, Samantha A -- Locher, Kaspar P -- England -- Nature. 2012 Oct 18;490(7420):367-72. doi: 10.1038/nature11442. Epub 2012 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biology and Biophysics, ETH Zurich, CH-8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23000901" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/*chemistry/genetics/metabolism ; Adenosine Triphosphatases/chemistry/metabolism ; Adenosine Triphosphate/metabolism ; Adenylyl Imidodiphosphate/chemistry/*metabolism ; Amino Acid Sequence ; Crystallography, X-Ray ; Cytoplasm/metabolism ; Disulfides/chemistry/metabolism ; Escherichia coli/*chemistry/genetics ; Escherichia coli Proteins/*chemistry/genetics/metabolism ; Magnesium/metabolism ; Models, Biological ; Models, Molecular ; Mutant Proteins/chemistry/genetics/metabolism ; Mutation ; Periplasmic Binding Proteins/*chemistry/genetics/metabolism ; Protein Binding ; Protein Conformation ; Protein Subunits/chemistry/genetics/metabolism ; Structure-Activity Relationship ; Vitamin B 12/chemistry/*metabolism
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    The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome (2012)
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    Publication Date: 2012-03-09
    Description: The recognition of distinctly modified histones by specialized 'effector' proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes. Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1--a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing--contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier-Gorlin syndrome (MGS), a form of primordial dwarfism, and ORC1 depletion in zebrafish results in an MGS-like phenotype. We find that wild-type human ORC1, but not ORC1-H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321094/" 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/PMC3321094/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kuo, Alex J -- Song, Jikui -- Cheung, Peggie -- Ishibe-Murakami, Satoko -- Yamazoe, Sayumi -- Chen, James K -- Patel, Dinshaw J -- Gozani, Or -- DP1 HD075622/HD/NICHD NIH HHS/ -- DP1 OD003792/OD/NIH HHS/ -- DP1 OD003792-04/OD/NIH HHS/ -- R01 GM079641/GM/NIGMS NIH HHS/ -- R01GM079641/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Mar 7;484(7392):115-9. doi: 10.1038/nature10956.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22398447" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carrier Proteins/genetics/metabolism ; Cell Cycle ; Cell Line ; Chromatin/genetics/metabolism ; Congenital Microtia ; Crystallography, X-Ray ; *DNA Replication/genetics ; Disease Models, Animal ; Dwarfism/genetics/metabolism ; Ear/abnormalities ; Growth Disorders/genetics/*metabolism ; Histones/*chemistry/genetics/*metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Micrognathism/genetics/*metabolism ; Models, Molecular ; Origin Recognition Complex/*chemistry/genetics/*metabolism ; Patella/abnormalities/metabolism ; Protein Structure, Tertiary ; Replication Origin ; Zebrafish ; Zebrafish Proteins/genetics/metabolism
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    Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106 (2012)
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    Publication Date: 2012-02-07
    Description: Dynamic variations in the structure of chromatin influence virtually all DNA-related processes in eukaryotes and are controlled in part by post-translational modifications of histones. One such modification, the acetylation of lysine 56 (H3K56ac) in the amino-terminal alpha-helix (alphaN) of histone H3, has been implicated in the regulation of nucleosome assembly during DNA replication and repair, and nucleosome disassembly during gene transcription. In Saccharomyces cerevisiae, the histone chaperone Rtt106 contributes to the deposition of newly synthesized H3K56ac-carrying H3-H4 complex on replicating DNA, but it is unclear how Rtt106 binds H3-H4 and specifically recognizes H3K56ac as there is no apparent acetylated lysine reader domain in Rtt106. Here, we show that two domains of Rtt106 are involved in a combinatorial recognition of H3-H4. An N-terminal domain homodimerizes and interacts with H3-H4 independently of acetylation while a double pleckstrin-homology (PH) domain binds the K56-containing region of H3. Affinity is markedly enhanced upon acetylation of K56, an effect that is probably due to increased conformational entropy of the alphaN helix of H3. Our data support a mode of interaction where the N-terminal homodimeric domain of Rtt106 intercalates between the two H3-H4 components of the (H3-H4)(2) tetramer while two double PH domains in the Rtt106 dimer interact with each of the two H3K56ac sites in (H3-H4)(2). We show that the Rtt106-(H3-H4)(2) interaction is important for gene silencing and the DNA damage response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3439842/" 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/PMC3439842/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Su, Dan -- Hu, Qi -- Li, Qing -- Thompson, James R -- Cui, Gaofeng -- Fazly, Ahmed -- Davies, Brian A -- Botuyan, Maria Victoria -- Zhang, Zhiguo -- Mer, Georges -- P50 CA108961/CA/NCI NIH HHS/ -- R01 CA132878/CA/NCI NIH HHS/ -- R01 CA132878-04/CA/NCI NIH HHS/ -- R01 GM072719/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Feb 5;483(7387):104-7. doi: 10.1038/nature10861.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22307274" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Binding Sites ; Crystallography, X-Ray ; DNA Damage ; Gene Silencing ; Genomic Instability ; Histones/*chemistry/*metabolism ; Lysine/analogs & derivatives/chemistry/metabolism ; Magnetic Resonance Spectroscopy ; Models, Molecular ; Molecular Chaperones/*chemistry/genetics/*metabolism ; Mutation/genetics ; Pliability ; Protein Binding ; Protein Multimerization ; Protein Structure, Tertiary ; Saccharomyces cerevisiae/*chemistry ; Saccharomyces cerevisiae Proteins/*chemistry/genetics/*metabolism ; Structure-Activity Relationship ; Substrate Specificity ; Xenopus laevis
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    Structural basis of ultraviolet-B perception by UVR8 (2012)
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    Publication Date: 2012-03-06
    Description: The Arabidopsis thaliana protein UVR8 is a photoreceptor for ultraviolet-B. Upon ultraviolet-B irradiation, UVR8 undergoes an immediate switch from homodimer to monomer, which triggers a signalling pathway for ultraviolet protection. The mechanism by which UVR8 senses ultraviolet-B remains largely unknown. Here we report the crystal structure of UVR8 at 1.8 A resolution, revealing a symmetric homodimer of seven-bladed beta-propeller that is devoid of any external cofactor as the chromophore. Arginine residues that stabilize the homodimeric interface, principally Arg 286 and Arg 338, make elaborate intramolecular cation-pi interactions with surrounding tryptophan amino acids. Two of these tryptophans, Trp 285 and Trp 233, collectively serve as the ultraviolet-B chromophore. Our structural and biochemical analyses identify the molecular mechanism for UVR8-mediated ultraviolet-B perception, in which ultraviolet-B radiation results in destabilization of the intramolecular cation-pi interactions, causing disruption of the critical intermolecular hydrogen bonds mediated by Arg 286 and Arg 338 and subsequent dissociation of the UVR8 homodimer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Di -- Hu, Qi -- Yan, Zhen -- Chen, Wen -- Yan, Chuangye -- Huang, Xi -- Zhang, Jing -- Yang, Panyu -- Deng, Haiteng -- Wang, Jiawei -- Deng, XingWang -- Shi, Yigong -- R37 GM047850/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Feb 29;484(7393):214-9. doi: 10.1038/nature10931.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tsinghua-Peking Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22388820" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*chemistry ; Arabidopsis Proteins/*chemistry/*radiation effects ; Cations/chemistry ; Chromosomal Proteins, Non-Histone/*chemistry/*radiation effects ; Crystallography, X-Ray ; Light Signal Transduction/*radiation effects ; Models, Molecular ; Protein Conformation/radiation effects ; Protein Multimerization/radiation effects ; Tryptophan/chemistry/metabolism ; *Ultraviolet Rays
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    X-ray structures of LeuT in substrate-free outward-open and apo inward-open states (2012)
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    Publication Date: 2012-01-11
    Description: Neurotransmitter sodium symporters are integral membrane proteins that remove chemical transmitters from the synapse and terminate neurotransmission mediated by serotonin, dopamine, noradrenaline, glycine and GABA (gamma-aminobutyric acid). Crystal structures of the bacterial homologue, LeuT, in substrate-bound outward-occluded and competitive inhibitor-bound outward-facing states have advanced our mechanistic understanding of neurotransmitter sodium symporters but have left fundamental questions unanswered. Here we report crystal structures of LeuT mutants in complexes with conformation-specific antibody fragments in the outward-open and inward-open states. In the absence of substrate but in the presence of sodium the transporter is outward-open, illustrating how the binding of substrate closes the extracellular gate through local conformational changes: hinge-bending movements of the extracellular halves of transmembrane domains 1, 2 and 6, together with translation of extracellular loop 4. The inward-open conformation, by contrast, involves large-scale conformational changes, including a reorientation of transmembrane domains 1, 2, 5, 6 and 7, a marked hinge bending of transmembrane domain 1a and occlusion of the extracellular vestibule by extracellular loop 4. These changes close the extracellular gate, open an intracellular vestibule, and largely disrupt the two sodium sites, thus providing a mechanism by which ions and substrate are released to the cytoplasm. The new structures establish a structural framework for the mechanism of neurotransmitter sodium symporters and their modulation by therapeutic and illicit substances.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306218/" 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/PMC3306218/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krishnamurthy, Harini -- Gouaux, Eric -- R37 MH070039/MH/NIMH NIH HHS/ -- R37 MH070039-09/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 9;481(7382):469-74. doi: 10.1038/nature10737.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22230955" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Monoclonal/immunology ; Antibody Specificity/immunology ; Apoproteins/*chemistry/genetics/immunology/metabolism ; Bacterial Proteins/*chemistry/genetics/immunology/metabolism ; Binding Sites ; Crystallography, X-Ray ; Immunoglobulin Fab Fragments/immunology ; Ions/chemistry ; Models, Molecular ; Movement ; Protein Conformation ; Sodium/chemistry/metabolism ; Structure-Activity Relationship ; Substrate Specificity
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    SbsB structure and lattice reconstruction unveil Ca2+ triggered S-layer assembly (2012)
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    Publication Date: 2012-06-23
    Description: S-layers are regular two-dimensional semipermeable protein layers that constitute a major cell-wall component in archaea and many bacteria. The nanoscale repeat structure of the S-layer lattices and their self-assembly from S-layer proteins (SLPs) have sparked interest in their use as patterning and display scaffolds for a range of nano-biotechnological applications. Despite their biological abundance and the technological interest in them, structural information about SLPs is limited to truncated and assembly-negative proteins. Here we report the X-ray structure of the SbsB SLP of Geobacillus stearothermophilus PV72/p2 by the use of nanobody-aided crystallization. SbsB consists of a seven-domain protein, formed by an amino-terminal cell-wall attachment domain and six consecutive immunoglobulin-like domains, that organize into a phi-shaped disk-like monomeric crystallization unit stabilized by interdomain Ca(2+) ion coordination. A Ca(2+)-dependent switch to the condensed SbsB quaternary structure pre-positions intermolecular contact zones and renders the protein competent for S-layer assembly. On the basis of crystal packing, chemical crosslinking data and cryo-electron microscopy projections, we present a model for the molecular organization of this SLP into a porous protein sheet inside the S-layer. The SbsB lattice represents a previously undescribed structural model for protein assemblies and may advance our understanding of SLP physiology and self-assembly, as well as the rational design of engineered higher-order structures for biotechnology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baranova, Ekaterina -- Fronzes, Remi -- Garcia-Pino, Abel -- Van Gerven, Nani -- Papapostolou, David -- Pehau-Arnaudet, Gerard -- Pardon, Els -- Steyaert, Jan -- Howorka, Stefan -- Remaut, Han -- BB/E010466/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2012 Jul 5;487(7405):119-22. doi: 10.1038/nature11155.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural and Molecular Microbiology, VIB Department of Structural Biology, VIB, Pleinlaan 2, 1050 Brussels, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722836" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; Calcium/chemistry/metabolism/*pharmacology ; Cryoelectron Microscopy ; Crystallization/methods ; Crystallography, X-Ray ; Geobacillus stearothermophilus/*chemistry ; Immunoglobulins/chemistry ; Membrane Proteins/*chemistry/*metabolism ; Models, Molecular ; Molecular Dynamics Simulation ; Nanostructures/chemistry ; Polymerization/drug effects ; Protein Structure, Quaternary/drug effects ; Protein Structure, Tertiary/drug effects ; Solutions
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    Evolution of the chalcone-isomerase fold from fatty-acid binding to stereospecific catalysis (2012)
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    Publication Date: 2012-05-25
    Description: Specialized metabolic enzymes biosynthesize chemicals of ecological importance, often sharing a pedigree with primary metabolic enzymes. However, the lineage of the enzyme chalcone isomerase (CHI) remained unknown. In vascular plants, CHI-catalysed conversion of chalcones to chiral (S)-flavanones is a committed step in the production of plant flavonoids, compounds that contribute to attraction, defence and development. CHI operates near the diffusion limit with stereospecific control. Although associated primarily with plants, the CHI fold occurs in several other eukaryotic lineages and in some bacteria. Here we report crystal structures, ligand-binding properties and in vivo functional characterization of a non-catalytic CHI-fold family from plants. Arabidopsis thaliana contains five actively transcribed genes encoding CHI-fold proteins, three of which additionally encode amino-terminal chloroplast-transit sequences. These three CHI-fold proteins localize to plastids, the site of de novo fatty-acid biosynthesis in plant cells. Furthermore, their expression profiles correlate with those of core fatty-acid biosynthetic enzymes, with maximal expression occurring in seeds and coinciding with increased fatty-acid storage in the developing embryo. In vitro, these proteins are fatty-acid-binding proteins (FAPs). FAP knockout A. thaliana plants show elevated alpha-linolenic acid levels and marked reproductive defects, including aberrant seed formation. Notably, the FAP discovery defines the adaptive evolution of a stereospecific and catalytically 'perfected' enzyme from a non-enzymatic ancestor over a defined period of plant evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880581/" 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/PMC3880581/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ngaki, Micheline N -- Louie, Gordon V -- Philippe, Ryan N -- Manning, Gerard -- Pojer, Florence -- Bowman, Marianne E -- Li, Ling -- Larsen, Elise -- Wurtele, Eve Syrkin -- Noel, Joseph P -- CA14195/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 13;485(7399):530-3. doi: 10.1038/nature11009.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Development, and Cell Biology, Iowa State University, Ames, Iowa 50011, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622584" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*chemistry/enzymology/genetics/growth & development ; Arabidopsis Proteins/chemistry/genetics/metabolism ; *Biocatalysis ; Crystallography, X-Ray ; *Evolution, Molecular ; Fatty Acid-Binding Proteins/chemistry/deficiency/genetics/metabolism ; Fatty Acids/*metabolism ; Intramolecular Lyases/*chemistry/deficiency/genetics/*metabolism ; Ligands ; Models, Molecular ; Phenotype ; Protein Binding ; *Protein Folding ; Stereoisomerism ; alpha-Linolenic Acid/metabolism
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    Crystal structure of a membrane-embedded H+-translocating pyrophosphatase (2012)
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    Publication Date: 2012-03-30
    Description: H(+)-translocating pyrophosphatases (H(+)-PPases) are active proton transporters that establish a proton gradient across the endomembrane by means of pyrophosphate (PP(i)) hydrolysis. H(+)-PPases are found primarily as homodimers in the vacuolar membrane of plants and the plasma membrane of several protozoa and prokaryotes. The three-dimensional structure and detailed mechanisms underlying the enzymatic and proton translocation reactions of H(+)-PPases are unclear. Here we report the crystal structure of a Vigna radiata H(+)-PPase (VrH(+)-PPase) in complex with a non-hydrolysable substrate analogue, imidodiphosphate (IDP), at 2.35 A resolution. Each VrH(+)-PPase subunit consists of an integral membrane domain formed by 16 transmembrane helices. IDP is bound in the cytosolic region of each subunit and trapped by numerous charged residues and five Mg(2+) ions. A previously undescribed proton translocation pathway is formed by six core transmembrane helices. Proton pumping can be initialized by PP(i) hydrolysis, and H(+) is then transported into the vacuolar lumen through a pathway consisting of Arg 242, Asp 294, Lys 742 and Glu 301. We propose a working model of the mechanism for the coupling between proton pumping and PP(i) hydrolysis by H(+)-PPases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Shih-Ming -- Tsai, Jia-Yin -- Hsiao, Chwan-Deng -- Huang, Yun-Tzu -- Chiu, Chen-Liang -- Liu, Mu-Hsuan -- Tung, Jung-Yu -- Liu, Tseng-Huang -- Pan, Rong-Long -- Sun, Yuh-Ju -- England -- Nature. 2012 Mar 28;484(7394):399-403. doi: 10.1038/nature10963.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Life Science and Institute of Bioinformatics and Structural Biology, College of Life Science, National Tsing Hua University, Hsinchu 30013, Taiwan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22456709" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Cytosol/metabolism ; Diphosphonates/chemistry/metabolism ; Fabaceae/*enzymology ; Hydrolysis ; Inorganic Pyrophosphatase/*chemistry/*metabolism ; Magnesium/metabolism ; Membrane Proteins/*chemistry/metabolism ; Models, Molecular ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Protons ; Static Electricity ; Vacuoles/metabolism
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    Enzymatic catalysis of anti-Baldwin ring closure in polyether biosynthesis (2012)
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    Publication Date: 2012-03-06
    Description: Polycyclic polyether natural products have fascinated chemists and biologists alike owing to their useful biological activity, highly complex structure and intriguing biosynthetic mechanisms. Following the original proposal for the polyepoxide origin of lasalocid and isolasalocid and the experimental determination of the origins of the oxygen and carbon atoms of both lasalocid and monensin, a unified stereochemical model for the biosynthesis of polyether ionophore antibiotics was proposed. The model was based on a cascade of nucleophilic ring closures of postulated polyepoxide substrates generated by stereospecific oxidation of all-trans polyene polyketide intermediates. Shortly thereafter, a related model was proposed for the biogenesis of marine ladder toxins, involving a series of nominally disfavoured anti-Baldwin, endo-tet epoxide-ring-opening reactions. Recently, we identified Lsd19 from the Streptomyces lasaliensis gene cluster as the epoxide hydrolase responsible for the epoxide-opening cyclization of bisepoxyprelasalocid A to form lasalocid A. Here we report the X-ray crystal structure of Lsd19 in complex with its substrate and product analogue to provide the first atomic structure-to our knowledge-of a natural enzyme capable of catalysing the disfavoured epoxide-opening cyclic ether formation. On the basis of our structural and computational studies, we propose a general mechanism for the enzymatic catalysis of polyether natural product biosynthesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401210/" 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/PMC3401210/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hotta, Kinya -- Chen, Xi -- Paton, Robert S -- Minami, Atsushi -- Li, Hao -- Swaminathan, Kunchithapadam -- Mathews, Irimpan I -- Watanabe, Kenji -- Oikawa, Hideaki -- Houk, Kendall N -- Kim, Chu-Young -- GM075962/GM/NIGMS NIH HHS/ -- R01 GM075962/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Mar 4;483(7389):355-8. doi: 10.1038/nature10865.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National University of Singapore, Department of Biological Sciences, 14 Science Drive 4, 117543 Singapore.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22388816" target="_blank"〉PubMed〈/a〉
    Keywords: *Biocatalysis ; Biological Products/chemistry/metabolism ; Crystallography, X-Ray ; Cyclization ; Epoxide Hydrolases/*chemistry/genetics/*metabolism ; Ethers/*chemistry/*metabolism ; Hydrogen Bonding ; Lasalocid/analogs & derivatives/*biosynthesis/*chemistry/metabolism ; Models, Molecular ; Molecular Structure ; Protein Conformation ; Streptomyces/genetics ; Structure-Activity Relationship
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    The structural biochemistry of Zucchini implicates it as a nuclease in piRNA biogenesis (2012)
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    Publication Date: 2012-10-16
    Description: PIWI-family proteins and their associated small RNAs (piRNAs) act in an evolutionarily conserved innate immune mechanism to provide essential protection for germ-cell genomes against the activity of mobile genetic elements. piRNA populations comprise a molecular definition of transposons, which permits them to distinguish transposons from host genes and selectively silence them. piRNAs can be generated in two distinct ways, forming either primary or secondary piRNAs. Primary piRNAs come from discrete genomic loci, termed piRNA clusters, and seem to be derived from long, single-stranded precursors. The biogenesis of primary piRNAs involves at least two nucleolytic steps. An unknown enzyme cleaves piRNA cluster transcripts to generate monophosphorylated piRNA 5' ends. piRNA 3' ends are probably formed by exonucleolytic trimming, after a piRNA precursor is loaded into its PIWI partner. Secondary piRNAs arise during the adaptive 'ping-pong' cycle, with their 5' termini being formed by the activity of PIWIs themselves. A number of proteins have been implicated genetically in primary piRNA biogenesis. One of these, Drosophila melanogaster Zucchini, is a member of the phospholipase-D family of phosphodiesterases, which includes both phospholipases and nucleases. Here we produced a dimeric, soluble fragment of the mouse Zucchini homologue (mZuc; also known as PLD6) and show that it possesses single-strand-specific nuclease activity. A crystal structure of mZuc at 1.75 A resolution indicates greater architectural similarity to phospholipase-D family nucleases than to phospholipases. Together, our data suggest that the Zucchini proteins act in primary piRNA biogenesis as nucleases, perhaps generating the 5' ends of primary piRNAs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493678/" 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/PMC3493678/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ipsaro, Jonathan J -- Haase, Astrid D -- Knott, Simon R -- Joshua-Tor, Leemor -- Hannon, Gregory J -- CA045508/CA/NCI NIH HHS/ -- F32 GM097888/GM/NIGMS NIH HHS/ -- F32GM97888/GM/NIGMS NIH HHS/ -- P30 CA045508/CA/NCI NIH HHS/ -- R01 GM062534/GM/NIGMS NIH HHS/ -- R01GM062534/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Nov 8;491(7423):279-83. doi: 10.1038/nature11502. Epub 2012 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉W. M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23064227" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Drosophila Proteins/chemistry/metabolism ; Endoribonucleases/chemistry/metabolism ; Mice ; Mitochondrial Proteins/*chemistry/*metabolism ; Models, Molecular ; Phospholipase D/*chemistry/*metabolism ; Protein Conformation ; Protein Multimerization ; RNA, Small Interfering/biosynthesis/chemistry/genetics/*metabolism ; Static Electricity ; Substrate Specificity
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    Structure of the carboxy-terminal region of a KCNH channel (2012)
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    Publication Date: 2012-01-11
    Description: The KCNH family of ion channels, comprising ether-a-go-go (EAG), EAG-related gene (ERG), and EAG-like (ELK) K(+)-channel subfamilies, is crucial for repolarization of the cardiac action potential, regulation of neuronal excitability and proliferation of tumour cells. The carboxy-terminal region of KCNH channels contains a cyclic-nucleotide-binding homology domain (CNBHD) and C-linker that couples the CNBHD to the pore. The C-linker/CNBHD is essential for proper function and trafficking of ion channels in the KCNH family. However, despite the importance of the C-linker/CNBHD for the function of KCNH channels, the structural basis of ion-channel regulation by the C-linker/CNBHD is unknown. Here we report the crystal structure of the C-linker/CNBHD of zebrafish ELK channels at 2.2-A resolution. Although the overall structure of the C-linker/CNBHD of ELK channels is similar to the cyclic-nucleotide-binding domain (CNBD) structure of the related hyperpolarization-activated cyclic-nucleotide-modulated (HCN) channels, there are marked differences. Unlike the CNBD of HCN, the CNBHD of ELK displays a negatively charged electrostatic profile that explains the lack of binding and regulation of KCNH channels by cyclic nucleotides. Instead of cyclic nucleotide, the binding pocket is occupied by a short beta-strand. Mutations of the beta-strand shift the voltage dependence of activation to more depolarized voltages, implicating the beta-strand as an intrinsic ligand for the CNBHD of ELK channels. In both ELK and HCN channels the C-linker is the site of virtually all of the intersubunit interactions in the C-terminal region. However, in the zebrafish ELK structure there is a reorientation in the C-linker so that the subunits form dimers instead of tetramers, as observed in HCN channels. These results provide a structural framework for understanding the regulation of ion channels in the KCNH family by the C-linker/CNBHD and may guide the design of specific drugs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267858/" 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/PMC3267858/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brelidze, Tinatin I -- Carlson, Anne E -- Sankaran, Banumathi -- Zagotta, William N -- F32 HL095241/HL/NHLBI NIH HHS/ -- F32 HL095241-03/HL/NHLBI NIH HHS/ -- R01 EY010329/EY/NEI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 9;481(7382):530-3. doi: 10.1038/nature10735.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Biophysics, University of Washington School of Medicine, Box 357290, Seattle, Washington 98195-7290, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22230959" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; Electrophysiological Phenomena ; Ether-A-Go-Go Potassium Channels/*chemistry/genetics/metabolism ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Ion Channels/chemistry ; Models, Molecular ; Mutation ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Static Electricity ; Structure-Activity Relationship ; Zebrafish ; Zebrafish Proteins/*chemistry/genetics/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Exploiting a natural conformational switch to engineer an interleukin-2 'superkine' (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-27
    Description: The immunostimulatory cytokine interleukin-2 (IL-2) is a growth factor for a wide range of leukocytes, including T cells and natural killer (NK) cells. Considerable effort has been invested in using IL-2 as a therapeutic agent for a variety of immune disorders ranging from AIDS to cancer. However, adverse effects have limited its use in the clinic. On activated T cells, IL-2 signals through a quaternary 'high affinity' receptor complex consisting of IL-2, IL-2Ralpha (termed CD25), IL-2Rbeta and IL-2Rgamma. Naive T cells express only a low density of IL-2Rbeta and IL-2Rgamma, and are therefore relatively insensitive to IL-2, but acquire sensitivity after CD25 expression, which captures the cytokine and presents it to IL-2Rbeta and IL-2Rgamma. Here, using in vitro evolution, we eliminated the functional requirement of IL-2 for CD25 expression by engineering an IL-2 'superkine' (also called super-2) with increased binding affinity for IL-2Rbeta. Crystal structures of the IL-2 superkine in free and receptor-bound forms showed that the evolved mutations are principally in the core of the cytokine, and molecular dynamics simulations indicated that the evolved mutations stabilized IL-2, reducing the flexibility of a helix in the IL-2Rbeta binding site, into an optimized receptor-binding conformation resembling that when bound to CD25. The evolved mutations in the IL-2 superkine recapitulated the functional role of CD25 by eliciting potent phosphorylation of STAT5 and vigorous proliferation of T cells irrespective of CD25 expression. Compared to IL-2, the IL-2 superkine induced superior expansion of cytotoxic T cells, leading to improved antitumour responses in vivo, and elicited proportionally less expansion of T regulatory cells and reduced pulmonary oedema. Collectively, we show that in vitro evolution has mimicked the functional role of CD25 in enhancing IL-2 potency and regulating target cell specificity, which has implications for immunotherapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338870/" 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/PMC3338870/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Levin, Aron M -- Bates, Darren L -- Ring, Aaron M -- Krieg, Carsten -- Lin, Jack T -- Su, Leon -- Moraga, Ignacio -- Raeber, Miro E -- Bowman, Gregory R -- Novick, Paul -- Pande, Vijay S -- Fathman, C Garrison -- Boyman, Onur -- Garcia, K Christopher -- AR050942/AR/NIAMS NIH HHS/ -- GM07365/GM/NIGMS NIH HHS/ -- R01 AI051321/AI/NIAID NIH HHS/ -- R01 AI051321-05/AI/NIAID NIH HHS/ -- R01 CA065237/CA/NCI NIH HHS/ -- R01-GM062868/GM/NIGMS NIH HHS/ -- R01AI51321/AI/NIAID NIH HHS/ -- R37 AI051321/AI/NIAID NIH HHS/ -- T32 AI007290/AI/NIAID NIH HHS/ -- U01 DK078123/DK/NIDDK NIH HHS/ -- U19 AI 082719/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 25;484(7395):529-33. doi: 10.1038/nature10975.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22446627" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Cell Line ; Cell Proliferation ; Crystallography, X-Ray ; *Directed Molecular Evolution ; Humans ; Immunotherapy ; Interleukin-2/*chemistry/genetics/*immunology/pharmacology ; Interleukin-2 Receptor alpha Subunit/chemistry/deficiency/immunology/metabolism ; Interleukin-2 Receptor beta Subunit/chemistry/metabolism ; Killer Cells, Natural/immunology ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Molecular Dynamics Simulation ; Mutant Proteins/*chemistry/genetics/*immunology/pharmacology ; Mutation ; Neoplasm Transplantation ; Neoplasms/drug therapy/immunology ; Phosphorylation ; Protein Conformation ; *Protein Engineering ; STAT5 Transcription Factor/metabolism ; Surface Plasmon Resonance ; T-Lymphocytes/cytology/immunology
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    Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans (2012)
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    Publication Date: 2012-09-25
    Description: P-glycoprotein (P-gp) is an ATP-binding cassette transporter that confers multidrug resistance in cancer cells. It also affects the absorption, distribution and clearance of cancer-unrelated drugs and xenobiotics. For these reasons, the structure and function of P-gp have been studied extensively for decades. Here we present biochemical characterization of P-gp from Caenorhabditis elegans and its crystal structure at a resolution of 3.4 angstroms. We find that the apparent affinities of P-gp for anticancer drugs actinomycin D and paclitaxel are approximately 4,000 and 100 times higher, respectively, in the membrane bilayer than in detergent. This affinity enhancement highlights the importance of membrane partitioning when a drug accesses the transporter in the membrane. Furthermore, the transporter in the crystal structure opens its drug pathway at the level of the membrane's inner leaflet. In the helices flanking the opening to the membrane, we observe extended loops that may mediate drug binding, function as hinges to gate the pathway or both. We also find that the interface between the transmembrane and nucleotide-binding domains, which couples ATP hydrolysis to transport, contains a ball-and-socket joint and salt bridges similar to the ATP-binding cassette importers, suggesting that ATP-binding cassette exporters and importers may use similar mechanisms to achieve alternating access for transport. Finally, a model of human P-gp derived from the structure of C. elegans P-gp not only is compatible with decades of biochemical analysis, but also helps to explain perplexing functional data regarding the Phe335Ala mutant. These results increase our understanding of the structure and function of this important molecule.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482266/" 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/PMC3482266/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jin, Mi Sun -- Oldham, Michael L -- Zhang, Qiuju -- Chen, Jue -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 25;490(7421):566-9. doi: 10.1038/nature11448. Epub 2012 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Purdue University, Indiana 47907, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23000902" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Binding Sites ; Caenorhabditis elegans/*chemistry ; Crystallography, X-Ray ; Dactinomycin/metabolism ; Humans ; Hydrolysis ; Lipid Bilayers/metabolism ; Models, Biological ; Models, Molecular ; P-Glycoprotein/*chemistry/metabolism ; Paclitaxel/metabolism ; Protein Structure, Tertiary ; Structural Homology, Protein ; Structure-Activity Relationship
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    Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis (2012)
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    Publication Date: 2012-07-31
    Description: Ubiquitin modification is mediated by a large family of specificity determining ubiquitin E3 ligases. To facilitate ubiquitin transfer, RING E3 ligases bind both substrate and a ubiquitin E2 conjugating enzyme linked to ubiquitin via a thioester bond, but the mechanism of transfer has remained elusive. Here we report the crystal structure of the dimeric RING domain of rat RNF4 in complex with E2 (UbcH5A) linked by an isopeptide bond to ubiquitin. While the E2 contacts a single protomer of the RING, ubiquitin is folded back onto the E2 by contacts from both RING protomers. The carboxy-terminal tail of ubiquitin is locked into an active site groove on the E2 by an intricate network of interactions, resulting in changes at the E2 active site. This arrangement is primed for catalysis as it can deprotonate the incoming substrate lysine residue and stabilize the consequent tetrahedral transition-state intermediate.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442243/" 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/PMC3442243/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Plechanovova, Anna -- Jaffray, Ellis G -- Tatham, Michael H -- Naismith, James H -- Hay, Ronald T -- 081862/Wellcome Trust/United Kingdom -- 098391/Wellcome Trust/United Kingdom -- 13067/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 Sep 6;489(7414):115-20. doi: 10.1038/nature11376.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22842904" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Hydrolysis ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; Mutation ; Nuclear Proteins/*chemistry/genetics/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Rats ; Transcription Factors/*chemistry/genetics/metabolism ; Ubiquitin/chemistry/genetics/*metabolism ; Ubiquitin-Conjugating Enzymes/*chemistry/genetics/*metabolism ; Ubiquitin-Protein Ligases/*chemistry/metabolism ; Ubiquitination ; *Zinc Fingers
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4 A (2012)
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    Publication Date: 2012-03-13
    Description: Nucleosides are required for DNA and RNA synthesis, and the nucleoside adenosine has a function in a variety of signalling processes. Transport of nucleosides across cell membranes provides the major source of nucleosides in many cell types and is also responsible for the termination of adenosine signalling. As a result of their hydrophilic nature, nucleosides require a specialized class of integral membrane proteins, known as nucleoside transporters (NTs), for specific transport across cell membranes. In addition to nucleosides, NTs are important determinants for the transport of nucleoside-derived drugs across cell membranes. A wide range of nucleoside-derived drugs, including anticancer drugs (such as Ara-C and gemcitabine) and antiviral drugs (such as zidovudine and ribavirin), have been shown to depend, at least in part, on NTs for transport across cell membranes. Concentrative nucleoside transporters, members of the solute carrier transporter superfamily SLC28, use an ion gradient in the active transport of both nucleosides and nucleoside-derived drugs against their chemical gradients. The structural basis for selective ion-coupled nucleoside transport by concentrative nucleoside transporters is unknown. Here we present the crystal structure of a concentrative nucleoside transporter from Vibrio cholerae in complex with uridine at 2.4 A. Our functional data show that, like its human orthologues, the transporter uses a sodium-ion gradient for nucleoside transport. The structure reveals the overall architecture of this class of transporter, unravels the molecular determinants for nucleoside and sodium binding, and provides a framework for understanding the mechanism of nucleoside and nucleoside drug transport across cell membranes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310960/" 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/PMC3310960/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johnson, Zachary Lee -- Cheong, Cheom-Gil -- Lee, Seok-Yong -- 1 DP2 OD008380-01/OD/NIH HHS/ -- DP2 OD008380/OD/NIH HHS/ -- DP2 OD008380-01/OD/NIH HHS/ -- R01 GM100984/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Mar 11;483(7390):489-93. doi: 10.1038/nature10882.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Ion Channel Research Unit, Duke University Medical Center, 2 Genome Court, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22407322" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Biological Transport ; Crystallography, X-Ray ; Humans ; Models, Molecular ; Nucleoside Transport Proteins/*chemistry/metabolism ; Nucleosides/metabolism ; Protein Conformation ; Protein Folding ; Sodium/metabolism ; Uridine/chemistry/metabolism ; Vibrio cholerae/*chemistry
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    HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle (2012)
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    Publication Date: 2012-08-14
    Description: Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder, caused by mutations in the cohesin-loading protein NIPBL for nearly 60% of individuals with classical CdLS, and by mutations in the core cohesin components SMC1A (~5%) and SMC3 (〈1%) for a smaller fraction of probands. In humans, the multisubunit complex cohesin is made up of SMC1, SMC3, RAD21 and a STAG protein. These form a ring structure that is proposed to encircle sister chromatids to mediate sister chromatid cohesion and also has key roles in gene regulation. SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin, and in yeast, the class I histone deacetylase Hos1 deacetylates SMC3 during anaphase. Here we identify HDAC8 as the vertebrate SMC3 deacetylase, as well as loss-of-function HDAC8 mutations in six CdLS probands. Loss of HDAC8 activity results in increased SMC3 acetylation and inefficient dissolution of the 'used' cohesin complex released from chromatin in both prophase and anaphase. SMC3 with retained acetylation is loaded onto chromatin, and chromatin immunoprecipitation sequencing analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443318/" 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/PMC3443318/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deardorff, Matthew A -- Bando, Masashige -- Nakato, Ryuichiro -- Watrin, Erwan -- Itoh, Takehiko -- Minamino, Masashi -- Saitoh, Katsuya -- Komata, Makiko -- Katou, Yuki -- Clark, Dinah -- Cole, Kathryn E -- De Baere, Elfride -- Decroos, Christophe -- Di Donato, Nataliya -- Ernst, Sarah -- Francey, Lauren J -- Gyftodimou, Yolanda -- Hirashima, Kyotaro -- Hullings, Melanie -- Ishikawa, Yuuichi -- Jaulin, Christian -- Kaur, Maninder -- Kiyono, Tohru -- Lombardi, Patrick M -- Magnaghi-Jaulin, Laura -- Mortier, Geert R -- Nozaki, Naohito -- Petersen, Michael B -- Seimiya, Hiroyuki -- Siu, Victoria M -- Suzuki, Yutaka -- Takagaki, Kentaro -- Wilde, Jonathan J -- Willems, Patrick J -- Prigent, Claude -- Gillessen-Kaesbach, Gabriele -- Christianson, David W -- Kaiser, Frank J -- Jackson, Laird G -- Hirota, Toru -- Krantz, Ian D -- Shirahige, Katsuhiko -- GM49758/GM/NIGMS NIH HHS/ -- K08 HD055488/HD/NICHD NIH HHS/ -- K08HD055488/HD/NICHD NIH HHS/ -- P01 HD052860/HD/NICHD NIH HHS/ -- R01 GM049758/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Sep 13;489(7415):313-7. doi: 10.1038/nature11316.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, Pennsylvania 19104, USA. deardorff@email.chop.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22885700" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Adaptor Proteins, Signal Transducing/metabolism ; Anaphase ; Binding Sites ; Cell Cycle Proteins/chemistry/*metabolism ; Chondroitin Sulfate Proteoglycans/chemistry/metabolism ; Chromatin/genetics/metabolism ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/chemistry/*metabolism ; Crystallography, X-Ray ; De Lange Syndrome/*genetics/*metabolism ; Female ; Fibroblasts ; HeLa Cells ; Histone Deacetylases/chemistry/deficiency/*genetics/metabolism ; Humans ; Male ; Models, Molecular ; Mutant Proteins/chemistry/genetics/metabolism ; Mutation/*genetics ; Nuclear Proteins/metabolism ; Phosphoproteins/metabolism ; Prophase ; Protein Conformation ; Proteins/genetics ; Repressor Proteins/chemistry/deficiency/*genetics/metabolism ; Transcription, Genetic
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    Structural basis for RNA-duplex recognition and unwinding by the DEAD-box helicase Mss116p (2012)
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    Publication Date: 2012-09-04
    Description: DEAD-box proteins are the largest family of nucleic acid helicases, and are crucial to RNA metabolism throughout all domains of life. They contain a conserved 'helicase core' of two RecA-like domains (domains (D)1 and D2), which uses ATP to catalyse the unwinding of short RNA duplexes by non-processive, local strand separation. This mode of action differs from that of translocating helicases and allows DEAD-box proteins to remodel large RNAs and RNA-protein complexes without globally disrupting RNA structure. However, the structural basis for this distinctive mode of RNA unwinding remains unclear. Here, structural, biochemical and genetic analyses of the yeast DEAD-box protein Mss116p indicate that the helicase core domains have modular functions that enable a novel mechanism for RNA-duplex recognition and unwinding. By investigating D1 and D2 individually and together, we find that D1 acts as an ATP-binding domain and D2 functions as an RNA-duplex recognition domain. D2 contains a nucleic-acid-binding pocket that is formed by conserved DEAD-box protein sequence motifs and accommodates A-form but not B-form duplexes, providing a basis for RNA substrate specificity. Upon a conformational change in which the two core domains join to form a 'closed state' with an ATPase active site, conserved motifs in D1 promote the unwinding of duplex substrates bound to D2 by excluding one RNA strand and bending the other. Our results provide a comprehensive structural model for how DEAD-box proteins recognize and unwind RNA duplexes. This model explains key features of DEAD-box protein function and affords a new perspective on how the evolutionarily related cores of other RNA and DNA helicases diverged to use different mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465527/" 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/PMC3465527/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mallam, Anna L -- Del Campo, Mark -- Gilman, Benjamin -- Sidote, David J -- Lambowitz, Alan M -- GM037951/GM/NIGMS NIH HHS/ -- R01 GM037951/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 4;490(7418):121-5. doi: 10.1038/nature11402. Epub 2012 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cellular and Molecular Biology, Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22940866" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/metabolism ; Adenosine Triphosphate/metabolism ; Amino Acid Motifs ; Base Sequence ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; DEAD-box RNA Helicases/*chemistry/*metabolism ; Evolution, Molecular ; GC Rich Sequence/genetics ; Models, Molecular ; *Nucleic Acid Conformation ; Protein Structure, Tertiary ; RNA, Double-Stranded/*chemistry/genetics/*metabolism ; RNA-Binding Proteins/chemistry/metabolism ; Saccharomyces cerevisiae/*enzymology ; Saccharomyces cerevisiae Proteins/*chemistry/*metabolism ; Structure-Activity Relationship ; Substrate Specificity
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    Crystal structure of the micro-opioid receptor bound to a morphinan antagonist (2012)
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    Publication Date: 2012-03-23
    Description: Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled micro-opioid receptor (micro-OR) in the central nervous system. Here we describe the 2.8 A crystal structure of the mouse micro-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the micro-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523197/" 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/PMC3523197/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Manglik, Aashish -- Kruse, Andrew C -- Kobilka, Tong Sun -- Thian, Foon Sun -- Mathiesen, Jesper M -- Sunahara, Roger K -- Pardo, Leonardo -- Weis, William I -- Kobilka, Brian K -- Granier, Sebastien -- DA031418/DA/NIDA NIH HHS/ -- NS028471/NS/NINDS NIH HHS/ -- R01 GM083118/GM/NIGMS NIH HHS/ -- R01 NS028471/NS/NINDS NIH HHS/ -- R21 DA031418/DA/NIDA NIH HHS/ -- England -- Nature. 2012 Mar 21;485(7398):321-6. doi: 10.1038/nature10954.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22437502" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Crystallography, X-Ray ; Ligands ; Mice ; Models, Molecular ; Morphinans/*chemistry/metabolism/pharmacology ; Protein Conformation ; Protein Multimerization ; Receptors, Opioid, mu/*antagonists & inhibitors/*chemistry/metabolism ; Solvents/chemistry
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 65
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    Crystallographic snapshot of cellulose synthesis and membrane translocation (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-12-12
    Description: Cellulose, the most abundant biological macromolecule, is an extracellular, linear polymer of glucose molecules. It represents an essential component of plant cell walls but is also found in algae and bacteria. In bacteria, cellulose production frequently correlates with the formation of biofilms, a sessile, multicellular growth form. Cellulose synthesis and transport across the inner bacterial membrane is mediated by a complex of the membrane-integrated catalytic BcsA subunit and the membrane-anchored, periplasmic BcsB protein. Here we present the crystal structure of a complex of BcsA and BcsB from Rhodobacter sphaeroides containing a translocating polysaccharide. The structure of the BcsA-BcsB translocation intermediate reveals the architecture of the cellulose synthase, demonstrates how BcsA forms a cellulose-conducting channel, and suggests a model for the coupling of cellulose synthesis and translocation in which the nascent polysaccharide is extended by one glucose molecule at a time.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542415/" 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/PMC3542415/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morgan, Jacob L W -- Strumillo, Joanna -- Zimmer, Jochen -- 1R01GM101001/GM/NIGMS NIH HHS/ -- R01 GM101001/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jan 10;493(7431):181-6. doi: 10.1038/nature11744. Epub 2012 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Membrane Biology, Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23222542" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacterial Proteins/*chemistry/*metabolism ; *Biocatalysis ; Biological Transport ; Catalytic Domain ; Cell Membrane/chemistry/*metabolism ; Cellulose/biosynthesis/*metabolism ; Crystallography, X-Ray ; Cyclic GMP/analogs & derivatives/metabolism/pharmacology ; Enzyme Activation/drug effects ; Models, Molecular ; Multiprotein Complexes/chemistry/metabolism ; Polysaccharides/metabolism ; Protein Structure, Tertiary ; Rhodobacter/*chemistry/cytology/enzymology/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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