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  • 1
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    Crystal structure of the polymerase PA(C)-PB1(N) complex from an avian influenza H5N1 virus (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-07-11
    Description: The recent emergence of highly pathogenic avian influenza A virus strains with subtype H5N1 pose a global threat to human health. Elucidation of the underlying mechanisms of viral replication is critical for development of anti-influenza virus drugs. The influenza RNA-dependent RNA polymerase (RdRp) heterotrimer has crucial roles in viral RNA replication and transcription. It contains three proteins: PA, PB1 and PB2. PB1 harbours polymerase and endonuclease activities and PB2 is responsible for cap binding; PA is implicated in RNA replication and proteolytic activity, although its function is less clearly defined. Here we report the 2.9 angstrom structure of avian H5N1 influenza A virus PA (PA(C), residues 257-716) in complex with the PA-binding region of PB1 (PB1(N), residues 1-25). PA(C) has a fold resembling a dragon's head with PB1(N) clamped into its open 'jaws'. PB1(N) is a known inhibitor that blocks assembly of the polymerase heterotrimer and abolishes viral replication. Our structure provides details for the binding of PB1(N) to PA(C) at the atomic level, demonstrating a potential target for novel anti-influenza therapeutics. We also discuss a potential nucleotide binding site and the roles of some known residues involved in polymerase activity. Furthermore, to explore the role of PA in viral replication and transcription, we propose a model for the influenza RdRp heterotrimer by comparing PA(C) with the lambda3 reovirus polymerase structure, and docking the PA(C) structure into an available low resolution electron microscopy map.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Xiaojing -- Zhou, Jie -- Bartlam, Mark -- Zhang, Rongguang -- Ma, Jianyuan -- Lou, Zhiyong -- Li, Xuemei -- Li, Jingjing -- Joachimiak, Andrzej -- Zeng, Zonghao -- Ge, Ruowen -- Rao, Zihe -- Liu, Yingfang -- England -- Nature. 2008 Aug 28;454(7208):1123-6. doi: 10.1038/nature07120. Epub 2008 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18615018" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Birds/*virology ; Crystallography, X-Ray ; Influenza A Virus, H5N1 Subtype/*enzymology ; Models, Molecular ; Multienzyme Complexes/chemistry/metabolism ; Nucleotides/metabolism ; Peptide Fragments/chemistry/metabolism ; Protein Binding ; Protein Structure, Quaternary ; RNA Replicase/*chemistry/metabolism ; Viral Proteins/*chemistry/*metabolism ; Virus Replication
    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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  • 2
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    Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-01-15
    Description: In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901986/" 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/PMC2901986/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jianming -- Adrian, Francisco J -- Jahnke, Wolfgang -- Cowan-Jacob, Sandra W -- Li, Allen G -- Iacob, Roxana E -- Sim, Taebo -- Powers, John -- Dierks, Christine -- Sun, Fangxian -- Guo, Gui-Rong -- Ding, Qiang -- Okram, Barun -- Choi, Yongmun -- Wojciechowski, Amy -- Deng, Xianming -- Liu, Guoxun -- Fendrich, Gabriele -- Strauss, Andre -- Vajpai, Navratna -- Grzesiek, Stephan -- Tuntland, Tove -- Liu, Yi -- Bursulaya, Badry -- Azam, Mohammad -- Manley, Paul W -- Engen, John R -- Daley, George Q -- Warmuth, Markus -- Gray, Nathanael S -- R01 CA130876/CA/NCI NIH HHS/ -- R01 CA130876-03/CA/NCI NIH HHS/ -- England -- Nature. 2010 Jan 28;463(7280):501-6. doi: 10.1038/nature08675. Epub 2010 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Department of Cancer Biology, Seeley G. Mudd Building 628, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20072125" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/*chemistry/metabolism/*pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; Benzamides ; Binding Sites ; Bone Marrow Transplantation ; Cell Line, Tumor ; Crystallization ; Disease Models, Animal ; Drug Resistance, Neoplasm/*drug effects ; Female ; Fusion Proteins, bcr-abl/*chemistry/genetics/metabolism ; Humans ; Imatinib Mesylate ; Inhibitory Concentration 50 ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug ; therapy/enzymology/*metabolism ; Male ; Mass Spectrometry ; Mice ; Models, Molecular ; Mutation/genetics ; Piperazines/chemistry/pharmacology ; Protein Structure, Tertiary ; Pyrimidines/chemistry/metabolism/pharmacology ; Transplantation, Heterologous
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Structural basis for the modular recognition of single-stranded RNA by PPR proteins (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-10-29
    Description: Pentatricopeptide repeat (PPR) proteins represent a large family of sequence-specific RNA-binding proteins that are involved in multiple aspects of RNA metabolism. PPR proteins, which are found in exceptionally large numbers in the mitochondria and chloroplasts of terrestrial plants, recognize single-stranded RNA (ssRNA) in a modular fashion. The maize chloroplast protein PPR10 binds to two similar RNA sequences from the ATPI-ATPH and PSAJ-RPL33 intergenic regions, referred to as ATPH and PSAJ, respectively. By protecting the target RNA elements from 5' or 3' exonucleases, PPR10 defines the corresponding 5' and 3' messenger RNA termini. Despite rigorous functional characterizations, the structural basis of sequence-specific ssRNA recognition by PPR proteins remains to be elucidated. Here we report the crystal structures of PPR10 in RNA-free and RNA-bound states at resolutions of 2.85 and 2.45 A, respectively. In the absence of RNA binding, the nineteen repeats of PPR10 are assembled into a right-handed superhelical spiral. PPR10 forms an antiparallel, intertwined homodimer and exhibits considerable conformational changes upon binding to its target ssRNA, an 18-nucleotide PSAJ element. Six nucleotides of PSAJ are specifically recognized by six corresponding PPR10 repeats following the predicted code. The molecular basis for the specific and modular recognition of RNA bases A, G and U is revealed. The structural elucidation of RNA recognition by PPR proteins provides an important framework for potential biotechnological applications of PPR proteins in RNA-related research areas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yin, Ping -- Li, Quanxiu -- Yan, Chuangye -- Liu, Ying -- Liu, Junjie -- Yu, Feng -- Wang, Zheng -- Long, Jiafu -- He, Jianhua -- Wang, Hong-Wei -- Wang, Jiawei -- Zhu, Jian-Kang -- Shi, Yigong -- Yan, Nieng -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Dec 5;504(7478):168-71. doi: 10.1038/nature12651. Epub 2013 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory of Bio-membrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China [2] Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24162847" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; *Models, Molecular ; Plant Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; RNA/chemistry/*metabolism ; Zea mays/*chemistry/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    The Mycobacterium tuberculosis regulatory network and hypoxia (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-07-05
    Description: We have taken the first steps towards a complete reconstruction of the Mycobacterium tuberculosis regulatory network based on ChIP-Seq and combined this reconstruction with system-wide profiling of messenger RNAs, proteins, metabolites and lipids during hypoxia and re-aeration. Adaptations to hypoxia are thought to have a prominent role in M. tuberculosis pathogenesis. Using ChIP-Seq combined with expression data from the induction of the same factors, we have reconstructed a draft regulatory network based on 50 transcription factors. This network model revealed a direct interconnection between the hypoxic response, lipid catabolism, lipid anabolism and the production of cell wall lipids. As a validation of this model, in response to oxygen availability we observe substantial alterations in lipid content and changes in gene expression and metabolites in corresponding metabolic pathways. The regulatory network reveals transcription factors underlying these changes, allows us to computationally predict expression changes, and indicates that Rv0081 is a regulatory hub.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087036/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4087036/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Galagan, James E -- Minch, Kyle -- Peterson, Matthew -- Lyubetskaya, Anna -- Azizi, Elham -- Sweet, Linsday -- Gomes, Antonio -- Rustad, Tige -- Dolganov, Gregory -- Glotova, Irina -- Abeel, Thomas -- Mahwinney, Chris -- Kennedy, Adam D -- Allard, Rene -- Brabant, William -- Krueger, Andrew -- Jaini, Suma -- Honda, Brent -- Yu, Wen-Han -- Hickey, Mark J -- Zucker, Jeremy -- Garay, Christopher -- Weiner, Brian -- Sisk, Peter -- Stolte, Christian -- Winkler, Jessica K -- Van de Peer, Yves -- Iazzetti, Paul -- Camacho, Diogo -- Dreyfuss, Jonathan -- Liu, Yang -- Dorhoi, Anca -- Mollenkopf, Hans-Joachim -- Drogaris, Paul -- Lamontagne, Julie -- Zhou, Yiyong -- Piquenot, Julie -- Park, Sang Tae -- Raman, Sahadevan -- Kaufmann, Stefan H E -- Mohney, Robert P -- Chelsky, Daniel -- Moody, D Branch -- Sherman, David R -- Schoolnik, Gary K -- HHSN272200800059C/AI/NIAID NIH HHS/ -- HHSN272200800059C/PHS HHS/ -- R01 AI 071155/AI/NIAID NIH HHS/ -- R01 AI071155/AI/NIAID NIH HHS/ -- U19 AI 076217/AI/NIAID NIH HHS/ -- U19 AI076217/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jul 11;499(7457):178-83. doi: 10.1038/nature12337. Epub 2013 Jul 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA. jgalag@bu.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23823726" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological ; Anoxia/*genetics/metabolism ; Bacterial Proteins/genetics/metabolism ; Binding Sites ; Chromatin Immunoprecipitation ; Gene Expression Profiling ; *Gene Regulatory Networks/genetics ; Genomics ; Lipid Metabolism/genetics ; Metabolic Networks and Pathways/*genetics ; Models, Biological ; Mycobacterium tuberculosis/drug effects/*genetics/*metabolism/physiology ; Oxygen/pharmacology ; Proteolysis ; RNA, Messenger/genetics/metabolism ; Reproducibility of Results ; Sequence Analysis, DNA ; Transcription Factors/genetics/metabolism ; Tuberculosis/metabolism/microbiology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Crystal structure of a copper-transporting PIB-type ATPase (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-07-01
    Description: Heavy-metal homeostasis and detoxification is crucial for cell viability. P-type ATPases of the class IB (PIB) are essential in these processes, actively extruding heavy metals from the cytoplasm of cells. Here we present the structure of a PIB-ATPase, a Legionella pneumophila CopA Cu(+)-ATPase, in a copper-free form, as determined by X-ray crystallography at 3.2 A resolution. The structure indicates a three-stage copper transport pathway involving several conserved residues. A PIB-specific transmembrane helix kinks at a double-glycine motif displaying an amphipathic helix that lines a putative copper entry point at the intracellular interface. Comparisons to Ca(2+)-ATPase suggest an ATPase-coupled copper release mechanism from the binding sites in the membrane via an extracellular exit site. The structure also provides a framework to analyse missense mutations in the human ATP7A and ATP7B proteins associated with Menkes' and Wilson's diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gourdon, Pontus -- Liu, Xiang-Yu -- Skjorringe, Tina -- Morth, J Preben -- Moller, Lisbeth Birk -- Pedersen, Bjorn Panyella -- Nissen, Poul -- England -- Nature. 2011 Jun 29;475(7354):59-64. doi: 10.1038/nature10191.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Aarhus University, Department of Molecular Biology, Gustav Wieds Vej 10C, DK-8000 Aarhus C, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21716286" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/genetics ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Biological Transport ; Calcium ; Cation Transport Proteins/genetics ; Cell Membrane/metabolism ; Copper/*metabolism ; Crystallography, X-Ray ; Cytoplasm/metabolism ; Hepatolenticular Degeneration/genetics ; Humans ; Legionella pneumophila/*chemistry ; Menkes Kinky Hair Syndrome/genetics ; Models, Molecular ; Mutation, Missense/genetics ; Protein Structure, Tertiary ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/chemistry ; Structure-Activity Relationship
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Notum deacylates Wnt proteins to suppress signalling activity (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-03-04
    Description: Signalling by Wnt proteins is finely balanced to ensure normal development and tissue homeostasis while avoiding diseases such as cancer. This is achieved in part by Notum, a highly conserved secreted feedback antagonist. Notum has been thought to act as a phospholipase, shedding glypicans and associated Wnt proteins from the cell surface. However, this view fails to explain specificity, as glypicans bind many extracellular ligands. Here we provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Structural analyses reveal glycosaminoglycan binding sites on Notum, which probably help Notum to co-localize with Wnt proteins. They also identify, at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palmitoleate. Kinetic and mass spectrometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins and thus constitutes the first known extracellular protein deacylase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376489/" 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/PMC4376489/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kakugawa, Satoshi -- Langton, Paul F -- Zebisch, Matthias -- Howell, Steven A -- Chang, Tao-Hsin -- Liu, Yan -- Feizi, Ten -- Bineva, Ganka -- O'Reilly, Nicola -- Snijders, Ambrosius P -- Jones, E Yvonne -- Vincent, Jean-Paul -- 090532/Wellcome Trust/United Kingdom -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 294523/European Research Council/International -- A10976/Cancer Research UK/United Kingdom -- C375/A10976/Cancer Research UK/United Kingdom -- G0900084/Medical Research Council/United Kingdom -- MC_U117584268/Medical Research Council/United Kingdom -- U117584268/Medical Research Council/United Kingdom -- WT093378MA/Wellcome Trust/United Kingdom -- WT099197MA/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Mar 12;519(7542):187-92. doi: 10.1038/nature14259. Epub 2015 Feb 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC's National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK. ; Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. ; Glycosciences Laboratory, Imperial College London, Department of Medicine, Du Cane Road, London W12 0NN, UK. ; Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. ; Cancer Research UK, Clare Hall Laboratories, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3LD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25731175" target="_blank"〉PubMed〈/a〉
    Keywords: Acylation ; Animals ; Binding Sites ; Carboxylesterase/chemistry/*metabolism ; Drosophila Proteins/chemistry/*metabolism ; Esterases/chemistry/genetics/*metabolism ; Fatty Acids, Monounsaturated/metabolism ; Glycosylphosphatidylinositols/metabolism ; Glypicans/metabolism ; Humans ; Kinetics ; Ligands ; Mass Spectrometry ; Models, Molecular ; Protein Binding ; Wnt Proteins/*chemistry/*metabolism ; *Wnt Signaling Pathway
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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