The crystal structure of Mycobacterium tuberculosis thymidylate kinase in complex with 3'-azidodeoxythymidine monophosphate suggests a mechanism for competitive inhibition
| Autor: | Dominique Bourgeois, E. Fioravanti, Hélène Munier-Lehmann, Virgile Adam |
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| Přispěvatelé: | Laboratoire de Cristallographie et Cristallogénèse des Protéines (LCCP), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Chimie Organique, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG) |
| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular MESH: Mycobacterium tuberculosis Protein Conformation azt activation MESH: DNA Replication tmp thymidine 01 natural sciences Biochemistry Thymidylate synthase Non-competitive inhibition MESH: Protein Conformation bacteria Magnesium ion 0303 health sciences Nucleoside-phosphate kinase common biology MESH: Kinetics electron-density maps MESH: Zidovudine MESH: Thymine Nucleotides 3. Good health [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology azidothymidine Zidovudine MESH: Models Molecular DNA Replication thymidine-5'-o-monophosphate analogs MESH: Binding Competitive Thymidylate kinase Binding Competitive Mycobacterium tuberculosis 03 medical and health sciences Thymine Nucleotides Binding site 030304 developmental biology Binding Sites 010405 organic chemistry Active site biology.organism_classification 0104 chemical sciences Kinetics MESH: Binding Sites kinetics biology.protein Nucleoside-Phosphate Kinase MESH: Nucleoside-Phosphate Kinase Dideoxynucleotides |
| Zdroj: | Biochemistry Biochemistry, American Chemical Society, 2005, 44 (1), pp.130-7. ⟨10.1021/bi0484163⟩ Biochemistry, 2005, 44 (1), pp.130-7. ⟨10.1021/bi0484163⟩ |
| ISSN: | 0006-2960 1520-4995 |
| DOI: | 10.1021/bi0484163⟩ |
| Popis: | Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis thymidylate kinase (TMPKMtub) catalyzes the ATP-dependent phosphorylation of deoxythymidine 5'-monophosphate (dTMP). Essential to DNA replication, this enzyme represents a promising target for developing new drugs against TB, because the configuration of its active site is unique within the TMPK family. Indeed, it has been proposed that, as opposed to other TMPKs, catalysis by TMPKMtub necessitates the transient binding of a magnesium ion coordinating the phosphate acceptor. Moreover, 3'-azidodeoxythymidine monophosphate (AZTMP) is a competitive inhibitor of TMPKMtub, whereas it is a substrate for human and other TMPKs. Here, the crystal structures of TMPKMtub in complex with deoxythymidine (dT) and AZTMP were determined to 2.1 and 2.0 Angstrom resolution, respectively, and suggest a mechanism for inhibition. The azido group of AZTMP perturbs the induced-fit mechanism normally adopted by the enzyme. Magnesium is prevented from binding, and the resulting electrostatic environment precludes phosphoryl transfer from occurring. Our data provide a model for drug development against tuberculosis. ispartof: Biochemistry vol:44 issue:1 pages:130-137 status: published |
| Databáze: | OpenAIRE |
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