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  • Articles  (36)
  • Crystallography, X-Ray  (36)
  • Nature Publishing Group (NPG)  (36)
  • 2005-2009  (36)
  • 1940-1944
  • Natural Sciences in General  (36)
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  • Articles  (36)
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  • 1
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    Cancer-associated IDH1 mutations produce 2-hydroxyglutarate (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-26
    Description: Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme's ability to catalyse conversion of isocitrate to alpha-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert alpha-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818760/" 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/PMC2818760/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dang, Lenny -- White, David W -- Gross, Stefan -- Bennett, Bryson D -- Bittinger, Mark A -- Driggers, Edward M -- Fantin, Valeria R -- Jang, Hyun Gyung -- Jin, Shengfang -- Keenan, Marie C -- Marks, Kevin M -- Prins, Robert M -- Ward, Patrick S -- Yen, Katharine E -- Liau, Linda M -- Rabinowitz, Joshua D -- Cantley, Lewis C -- Thompson, Craig B -- Vander Heiden, Matthew G -- Su, Shinsan M -- P01 CA104838/CA/NCI NIH HHS/ -- P01 CA104838-05/CA/NCI NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 CA105463/CA/NCI NIH HHS/ -- R01 CA105463-06/CA/NCI NIH HHS/ -- R21 CA128620/CA/NCI NIH HHS/ -- England -- Nature. 2009 Dec 10;462(7274):739-44. doi: 10.1038/nature08617. Epub .〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19935646" target="_blank"〉PubMed〈/a〉
    Keywords: Arginine/genetics ; Brain Neoplasms/*genetics/*metabolism/pathology ; Catalytic Domain ; Cell Line ; Crystallography, X-Ray ; Disease Progression ; Enzyme Assays ; Glioma/genetics/metabolism/pathology ; Glutarates/*metabolism ; Histidine/genetics/metabolism ; Humans ; Isocitrate Dehydrogenase/*genetics/*metabolism ; Ketoglutaric Acids/metabolism ; Models, Molecular ; Mutant Proteins/*genetics/*metabolism ; Mutation/genetics ; Protein Conformation
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Crystal structure of DNA-PKcs reveals a large open-ring cradle comprised of HEAT repeats (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-12-22
    Description: Broken chromosomes arising from DNA double-strand breaks result from endogenous events such as the production of reactive oxygen species during cellular metabolism, as well as from exogenous sources such as ionizing radiation. Left unrepaired or incorrectly repaired they can lead to genomic changes that may result in cell death or cancer. DNA-dependent protein kinase (DNA-PK), a holoenzyme that comprises the DNA-PK catalytic subunit (DNA-PKcs) and the heterodimer Ku70/Ku80, has a major role in non-homologous end joining-the main pathway in mammals used to repair double-strand breaks. DNA-PKcs is a serine/threonine protein kinase comprising a single polypeptide chain of 4,128 amino acids and belonging to the phosphatidylinositol-3-OH kinase (PI(3)K)-related protein family. DNA-PKcs is involved in the sensing and transmission of DNA damage signals to proteins such as p53, setting off events that lead to cell cycle arrest. It phosphorylates a wide range of substrates in vitro, including Ku70/Ku80, which is translocated along DNA. Here we present the crystal structure of human DNA-PKcs at 6.6 A resolution, in which the overall fold is clearly visible, to our knowledge, for the first time. The many alpha-helical HEAT repeats (helix-turn-helix motifs) facilitate bending and allow the polypeptide chain to fold into a hollow circular structure. The carboxy-terminal kinase domain is located on top of this structure, and a small HEAT repeat domain that probably binds DNA is inside. The structure provides a flexible cradle to promote DNA double-strand-break repair.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2811870/" 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/PMC2811870/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sibanda, Bancinyane L -- Chirgadze, Dimitri Y -- Blundell, Tom L -- 079281/Wellcome Trust/United Kingdom -- A3846/Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Jan 7;463(7277):118-21. doi: 10.1038/nature08648. Epub 2009 Dec 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Cambridge, Old Addenbrooke's site, 80 Tennis Court Road, Cambridge CB2 1GA, UK. lynn@cryst.bioc.cam.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20023628" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, Nuclear/chemistry ; Catalytic Domain ; Crystallography, X-Ray ; DNA/metabolism ; DNA Breaks, Double-Stranded ; DNA-Activated Protein Kinase/*chemistry/metabolism ; DNA-Binding Proteins/chemistry ; HeLa Cells ; *Helix-Turn-Helix Motifs ; Humans ; Models, Molecular ; Nuclear Proteins/*chemistry/metabolism ; Protein Folding ; Protein Structure, Secondary
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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 recognition and functional activation of FcgammaR by innate pentraxins (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-11-18
    Description: Pentraxins are a family of ancient innate immune mediators conserved throughout evolution. The classical pentraxins include serum amyloid P component (SAP) and C-reactive protein, which are two of the acute-phase proteins synthesized in response to infection. Both recognize microbial pathogens and activate the classical complement pathway through C1q (refs 3 and 4). More recently, members of the pentraxin family were found to interact with cell-surface Fcgamma receptors (FcgammaR) and activate leukocyte-mediated phagocytosis. Here we describe the structural mechanism for pentraxin's binding to FcgammaR and its functional activation of FcgammaR-mediated phagocytosis and cytokine secretion. The complex structure between human SAP and FcgammaRIIa reveals a diagonally bound receptor on each SAP pentamer with both D1 and D2 domains of the receptor contacting the ridge helices from two SAP subunits. The 1:1 stoichiometry between SAP and FcgammaRIIa infers the requirement for multivalent pathogen binding for receptor aggregation. Mutational and binding studies show that pentraxins are diverse in their binding specificity for FcgammaR isoforms but conserved in their recognition structure. The shared binding site for SAP and IgG results in competition for FcgammaR binding and the inhibition of immune-complex-mediated phagocytosis by soluble pentraxins. These results establish antibody-like functions for pentraxins in the FcgammaR pathway, suggest an evolutionary overlap between the innate and adaptive immune systems, and have new therapeutic implications for autoimmune diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688732/" 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/PMC2688732/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Jinghua -- Marnell, Lorraine L -- Marjon, Kristopher D -- Mold, Carolyn -- Du Clos, Terry W -- Sun, Peter D -- R01 AI28358/AI/NIAID NIH HHS/ -- T32 AI007538/AI/NIAID NIH HHS/ -- Z01 AI000853-09/Intramural NIH HHS/ -- England -- Nature. 2008 Dec 18;456(7224):989-92. doi: 10.1038/nature07468. Epub 2008 Nov 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19011614" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Binding, Competitive ; C-Reactive Protein/chemistry/*immunology/*metabolism ; Crystallography, X-Ray ; Cytokines/immunology/secretion ; Humans ; Immunity, Innate/*immunology ; Immunoglobulin G/immunology/metabolism ; Macrophages/cytology/immunology ; Models, Molecular ; Phagocytosis ; Protein Conformation ; Receptors, IgG/chemistry/*immunology/*metabolism ; Serum Amyloid P-Component/chemistry/*immunology/*metabolism
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  • 4
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    Structural basis for the function and inhibition of an influenza virus proton channel (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-02-01
    Description: The M2 protein from influenza A virus is a pH-activated proton channel that mediates acidification of the interior of viral particles entrapped in endosomes. M2 is the target of the anti-influenza drugs amantadine and rimantadine; recently, resistance to these drugs in humans, birds and pigs has reached more than 90% (ref. 1). Here we describe the crystal structure of the transmembrane-spanning region of the homotetrameric protein in the presence and absence of the channel-blocking drug amantadine. pH-dependent structural changes occur near a set of conserved His and Trp residues that are involved in proton gating. The drug-binding site is lined by residues that are mutated in amantadine-resistant viruses. Binding of amantadine physically occludes the pore, and might also perturb the pK(a) of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2-channel blockers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3889492/" 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/PMC3889492/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stouffer, Amanda L -- Acharya, Rudresh -- Salom, David -- Levine, Anna S -- Di Costanzo, Luigi -- Soto, Cinque S -- Tereshko, Valentina -- Nanda, Vikas -- Stayrook, Steven -- DeGrado, William F -- R37 GM054616/GM/NIGMS NIH HHS/ -- T32 GM008275/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Jan 31;451(7178):596-9. doi: 10.1038/nature06528.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18235504" target="_blank"〉PubMed〈/a〉
    Keywords: Amantadine/chemistry/metabolism/pharmacology ; Crystallography, X-Ray ; Drug Resistance, Viral/genetics ; Histidine/metabolism ; Hydrogen-Ion Concentration ; Influenza A virus/*chemistry/genetics/metabolism ; Ion Channel Gating/drug effects ; Models, Molecular ; Protein Structure, Quaternary ; Protons ; Structure-Activity Relationship ; Tryptophan/metabolism ; Viral Matrix Proteins/*antagonists & inhibitors/*chemistry/genetics/metabolism
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  • 5
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    Crystal structure of the ZP-N domain of ZP3 reveals the core fold of animal egg coats (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-12-05
    Description: Species-specific recognition between the egg extracellular matrix (zona pellucida) and sperm is the first, crucial step of mammalian fertilization. Zona pellucida filament components ZP3 and ZP2 act as sperm receptors, and mice lacking either of the corresponding genes produce oocytes without a zona pellucida and are completely infertile. Like their counterparts in the vitelline envelope of non-mammalian eggs and many other secreted eukaryotic proteins, zona pellucida subunits polymerize using a 'zona pellucida (ZP) domain' module, whose conserved amino-terminal part (ZP-N) was suggested to constitute a domain of its own. No atomic structure has been reported for ZP domain proteins, and there is no structural information on any conserved vertebrate protein that is essential for fertilization and directly involved in egg-sperm binding. Here we describe the 2.3 angstrom (A) resolution structure of the ZP-N fragment of mouse primary sperm receptor ZP3. The ZP-N fold defines a new immunoglobulin superfamily subtype with a beta-sheet extension characterized by an E' strand and an invariant tyrosine residue implicated in polymerization. The structure strongly supports the presence of ZP-N repeats within the N-terminal region of ZP2 and other vertebrate zona pellucida/vitelline envelope proteins, with implications for overall egg coat architecture, the post-fertilization block to polyspermy and speciation. Moreover, it provides an important framework for understanding human diseases caused by mutations in ZP domain proteins and developing new methods of non-hormonal contraception.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Monne, Magnus -- Han, Ling -- Schwend, Thomas -- Burendahl, Sofia -- Jovine, Luca -- G0500367/Medical Research Council/United Kingdom -- England -- Nature. 2008 Dec 4;456(7222):653-7. doi: 10.1038/nature07599.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Karolinska Institutet, Department of Biosciences and Nutrition, Halsovagen 7, SE-141 57 Huddinge, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052627" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Binding Sites ; CHO Cells ; Conserved Sequence ; Cricetinae ; Cricetulus ; Crystallization ; Crystallography, X-Ray ; Egg Proteins/*chemistry/genetics/*metabolism ; Female ; Male ; Membrane Glycoproteins/*chemistry/genetics/*metabolism ; Mice ; Models, Molecular ; Molecular Sequence Data ; Ovum/*chemistry/*metabolism ; Peptide Fragments/chemistry/genetics/metabolism ; Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Cell Surface/*chemistry/genetics/*metabolism ; Repetitive Sequences, Amino Acid ; Spermatozoa/metabolism
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  • 6
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    Kemp elimination catalysts by computational enzyme design (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-03-21
    Description: The design of new enzymes for reactions not catalysed by naturally occurring biocatalysts is a challenge for protein engineering and is a critical test of our understanding of enzyme catalysis. Here we describe the computational design of eight enzymes that use two different catalytic motifs to catalyse the Kemp elimination-a model reaction for proton transfer from carbon-with measured rate enhancements of up to 10(5) and multiple turnovers. Mutational analysis confirms that catalysis depends on the computationally designed active sites, and a high-resolution crystal structure suggests that the designs have close to atomic accuracy. Application of in vitro evolution to enhance the computational designs produced a 〉200-fold increase in k(cat)/K(m) (k(cat)/K(m) of 2,600 M(-1)s(-1) and k(cat)/k(uncat) of 〉10(6)). These results demonstrate the power of combining computational protein design with directed evolution for creating new enzymes, and we anticipate the creation of a wide range of useful new catalysts in the future.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rothlisberger, Daniela -- Khersonsky, Olga -- Wollacott, Andrew M -- Jiang, Lin -- DeChancie, Jason -- Betker, Jamie -- Gallaher, Jasmine L -- Althoff, Eric A -- Zanghellini, Alexandre -- Dym, Orly -- Albeck, Shira -- Houk, Kendall N -- Tawfik, Dan S -- Baker, David -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 May 8;453(7192):190-5. doi: 10.1038/nature06879. Epub 2008 Mar 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18354394" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Amino Acid Motifs ; Binding Sites/genetics ; Catalysis ; Computational Biology ; *Computer Simulation ; Crystallography, X-Ray ; Directed Molecular Evolution/*methods ; Drug Design ; Drug Evaluation, Preclinical ; Enzymes/*chemistry/genetics/*metabolism ; Kinetics ; Models, Chemical ; Models, Molecular ; Protein Engineering/*methods ; Quantum Theory ; Sensitivity and Specificity
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  • 7
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    Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-11-21
    Description: Calpains are non-lysosomal calcium-dependent cysteine proteinases that selectively cleave proteins in response to calcium signals and thereby control cellular functions such as cytoskeletal remodelling, cell cycle progression, gene expression and apoptotic cell death. In mammals, the two best-characterized members of the calpain family, calpain 1 and calpain 2 (micro-calpain and m-calpain, respectively), are ubiquitously expressed. The activity of calpains is tightly controlled by the endogenous inhibitor calpastatin, which is an intrinsically unstructured protein capable of reversibly binding and inhibiting four molecules of calpain, but only in the presence of calcium. To date, the mechanism of inhibition by calpastatin and the basis for its absolute specificity have remained speculative. It was not clear how this unstructured protein inhibits calpains without being cleaved itself, nor was it known how calcium induced changes that facilitated the binding of calpastatin to calpain. Here we report the 2.4-A-resolution crystal structure of the calcium-bound calpain 2 heterodimer bound by one of the four inhibitory domains of calpastatin. Calpastatin is seen to inhibit calpain by occupying both sides of the active site cleft. Although the inhibitor passes through the active site cleft it escapes cleavage in a novel manner by looping out and around the active site cysteine. The inhibitory domain of calpastatin recognizes multiple lower affinity sites present only in the calcium-bound form of the enzyme, resulting in an interaction that is tight, specific and calcium dependent. This crystal structure, and that of a related complex, also reveal the conformational changes that calpain undergoes on binding calcium, which include opening of the active site cleft and movement of the domains relative to each other to produce a more compact enzyme.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hanna, Rachel A -- Campbell, Robert L -- Davies, Peter L -- England -- Nature. 2008 Nov 20;456(7220):409-12. doi: 10.1038/nature07451.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19020623" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/*metabolism ; Calcium-Binding Proteins/*chemistry/*metabolism ; Calpain/*antagonists & inhibitors/*chemistry/metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Models, Molecular ; Protein Binding ; Protein Multimerization ; Rats ; Structure-Activity Relationship
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  • 8
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    Crystal structure of the anti-viral APOBEC3G catalytic domain and functional implications (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-10-14
    Description: The APOBEC family members are involved in diverse biological functions. APOBEC3G restricts the replication of human immunodeficiency virus (HIV), hepatitis B virus and retroelements by cytidine deamination on single-stranded DNA or by RNA binding. Here we report the high-resolution crystal structure of the carboxy-terminal deaminase domain of APOBEC3G (APOBEC3G-CD2) purified from Escherichia coli. The APOBEC3G-CD2 structure has a five-stranded beta-sheet core that is common to all known deaminase structures and closely resembles the structure of another APOBEC protein, APOBEC2 (ref. 5). A comparison of APOBEC3G-CD2 with other deaminase structures shows a structural conservation of the active-site loops that are directly involved in substrate binding. In the X-ray structure, these APOBEC3G active-site loops form a continuous 'substrate groove' around the active centre. The orientation of this putative substrate groove differs markedly (by 90 degrees) from the groove predicted by the NMR structure. We have introduced mutations around the groove, and have identified residues involved in substrate specificity, single-stranded DNA binding and deaminase activity. These results provide a basis for understanding the underlying mechanisms of substrate specificity for the APOBEC family.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714533/" 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/PMC2714533/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Holden, Lauren G -- Prochnow, Courtney -- Chang, Y Paul -- Bransteitter, Ronda -- Chelico, Linda -- Sen, Udayaditya -- Stevens, Raymond C -- Goodman, Myron F -- Chen, Xiaojiang S -- R01 AI055926/AI/NIAID NIH HHS/ -- R01 AI055926-05/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Nov 6;456(7218):121-4. doi: 10.1038/nature07357. Epub 2008 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18849968" target="_blank"〉PubMed〈/a〉
    Keywords: Antiviral Agents ; *Catalytic Domain ; Crystallography, X-Ray ; Cytidine Deaminase/*chemistry/genetics/isolation & purification/*metabolism ; DNA, Single-Stranded/metabolism ; Escherichia coli ; Humans ; Models, Molecular ; Muscle Proteins/chemistry ; Mutant Proteins/chemistry/genetics/metabolism ; Mutation ; Nuclear Magnetic Resonance, Biomolecular ; Protein Structure, Secondary ; Structural Homology, Protein ; Structure-Activity Relationship ; Substrate Specificity
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  • 9
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    Flipping of alkylated DNA damage bridges base and nucleotide excision repair (2009)
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    Publication Date: 2009-06-12
    Description: Alkyltransferase-like proteins (ATLs) share functional motifs with the cancer chemotherapy target O(6)-alkylguanine-DNA alkyltransferase (AGT) and paradoxically protect cells from the biological effects of DNA alkylation damage, despite lacking the reactive cysteine and alkyltransferase activity of AGT. Here we determine Schizosaccharomyces pombe ATL structures without and with damaged DNA containing the endogenous lesion O(6)-methylguanine or cigarette-smoke-derived O(6)-4-(3-pyridyl)-4-oxobutylguanine. These results reveal non-enzymatic DNA nucleotide flipping plus increased DNA distortion and binding pocket size compared to AGT. Our analysis of lesion-binding site conservation identifies new ATLs in sea anemone and ancestral archaea, indicating that ATL interactions are ancestral to present-day repair pathways in all domains of life. Genetic connections to mammalian XPG (also known as ERCC5) and ERCC1 in S. pombe homologues Rad13 and Swi10 and biochemical interactions with Escherichia coli UvrA and UvrC combined with structural results reveal that ATLs sculpt alkylated DNA to create a genetic and structural intersection of base damage processing with nucleotide excision repair.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729916/" 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/PMC2729916/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tubbs, Julie L -- Latypov, Vitaly -- Kanugula, Sreenivas -- Butt, Amna -- Melikishvili, Manana -- Kraehenbuehl, Rolf -- Fleck, Oliver -- Marriott, Andrew -- Watson, Amanda J -- Verbeek, Barbara -- McGown, Gail -- Thorncroft, Mary -- Santibanez-Koref, Mauro F -- Millington, Christopher -- Arvai, Andrew S -- Kroeger, Matthew D -- Peterson, Lisa A -- Williams, David M -- Fried, Michael G -- Margison, Geoffrey P -- Pegg, Anthony E -- Tainer, John A -- CA018137/CA/NCI NIH HHS/ -- CA097209/CA/NCI NIH HHS/ -- CA59887/CA/NCI NIH HHS/ -- GM070662/GM/NIGMS NIH HHS/ -- R01 CA059887/CA/NCI NIH HHS/ -- R01 CA059887-12/CA/NCI NIH HHS/ -- R01 CA059887-13/CA/NCI NIH HHS/ -- R01 GM070662/GM/NIGMS NIH HHS/ -- R01 GM070662-01/GM/NIGMS NIH HHS/ -- R01 GM070662-02/GM/NIGMS NIH HHS/ -- R01 GM070662-03/GM/NIGMS NIH HHS/ -- R01 GM070662-04/GM/NIGMS NIH HHS/ -- R01 GM070662-05/GM/NIGMS NIH HHS/ -- R01 GM070662-06/GM/NIGMS NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2009 Jun 11;459(7248):808-13. doi: 10.1038/nature08076.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Skaggs Institute for Chemical Biology and 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/19516334" target="_blank"〉PubMed〈/a〉
    Keywords: Alkyl and Aryl Transferases/*chemistry/*metabolism ; Alkylation ; Binding Sites ; Crystallography, X-Ray ; DNA/chemistry/metabolism ; *DNA Damage ; *DNA Repair ; Guanine/analogs & derivatives/chemistry/metabolism ; Humans ; Models, Molecular ; Protein Binding ; Protein Conformation
    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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    An unexpected twist in viral capsid maturation (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-02-11
    Description: Lambda-like double-stranded (ds) DNA bacteriophage undergo massive conformational changes in their capsid shell during the packaging of their viral genomes. Capsid shells are complex organizations of hundreds of protein subunits that assemble into intricate quaternary complexes that ultimately are able to withstand over 50 atm of pressure during genome packaging. The extensive integration between subunits in capsids requires the formation of an intermediate complex, termed a procapsid, from which individual subunits can undergo the necessary refolding and structural rearrangements needed to transition to the more stable capsid. Although various mature capsids have been characterized at atomic resolution, no such procapsid structure is available for a dsDNA virus or bacteriophage. Here we present a procapsid X-ray structure at 3.65 A resolution, termed prohead II, of the lambda-like bacteriophage HK97, the mature capsid structure of which was previously solved to 3.44 A (ref. 2). A comparison of the two largely different capsid forms has unveiled an unprecedented expansion mechanism that describes the transition. Crystallographic and hydrogen/deuterium exchange data presented here demonstrate that the subunit tertiary structures are significantly different between the two states, with twisting and bending motions occurring in both helical and beta-sheet regions. We also identified subunit interactions at each three-fold axis of the capsid that are maintained throughout maturation. The interactions sustain capsid integrity during subunit refolding and provide a fixed hinge from which subunits undergo rotational and translational motions during maturation. Previously published calorimetric data of a closely related bacteriophage, P22, showed that capsid maturation was an exothermic process that resulted in a release of 90 kJ mol(-1) of energy. We propose that the major tertiary changes presented in this study reveal a structural basis for an exothermic maturation process probably present in many dsDNA bacteriophage and possibly viruses such as herpesvirus, which share the HK97 subunit fold.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2765791/" 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/PMC2765791/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gertsman, Ilya -- Gan, Lu -- Guttman, Miklos -- Lee, Kelly -- Speir, Jeffrey A -- Duda, Robert L -- Hendrix, Roger W -- Komives, Elizabeth A -- Johnson, John E -- GM08326/GM/NIGMS NIH HHS/ -- R01 AI040101/AI/NIAID NIH HHS/ -- R01 AI040101-04/AI/NIAID NIH HHS/ -- R01 AI040101-14/AI/NIAID NIH HHS/ -- R01 AI40101/AI/NIAID NIH HHS/ -- R01 GM47795/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Apr 2;458(7238):646-50. doi: 10.1038/nature07686. Epub 2009 Feb 8.〈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/19204733" target="_blank"〉PubMed〈/a〉
    Keywords: Capsid/*chemistry/*metabolism ; Capsid Proteins/chemistry/genetics/metabolism ; Crystallography, X-Ray ; Deuterium Exchange Measurement ; Models, Molecular ; Movement ; Protein Conformation ; Protein Folding ; Protein Multimerization ; Protein Subunits/chemistry/metabolism ; Siphoviridae/*chemistry/genetics/*growth & development ; Thermodynamics ; *Virus Assembly
    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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