Use of allostery to identify inhibitors of calmodulin-induced activation of Bacillus anthracis edema factor
| Autor: | Arnaud Blondel, Elodie Laine, Wei-Jen Tang, Daniel Ladant, Thérèse E. Malliavin, Johanna C. Karst, Christophe Goncalves, Aurélien Lesnard, Sylvain Rault |
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| Přispěvatelé: | Bioinformatique Structurale, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Biochimie des Interactions Macromoléculaires / Biochemistry of Macromolecular Interactions, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Ben May Department for Cancer Research, University of Chicago, The French National Chemical Library and, in particular, Prof. Marcel Hibert, Dr. Bruno Didier, Dr. Philippe Jauffret, and Mr. Kiet Tran are gratefully acknowledged. Dr. David Giganti indicated useful references. This work was supported by the French Ministry of Defense (Direction Générale de l’Armement - Mission pour la Recherche et l’Innovation Scientifique), the Centre National de la Recherche Scientifique, and Institut Pasteur. Molecular dynamics calculations were performed by means of an allocation from the Centre National de la Recherche Scientifique Institut du Développement et des Ressources en Informatique Scientifique supercomputing center, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Biochimie des Interactions Macromoléculaires, Centre d'Etudes et de Recherche sur le Médicament de Normandie ( CERMN ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular MESH : Drug Design Protein Conformation Chemistry Pharmaceutical MESH : Chemistry Pharmaceutical MESH : Allosteric Site MESH: Drug Design inhibition of protein–protein association 01 natural sciences Bordetella pertussis Adenylyl cyclase MESH: Bordetella pertussis chemistry.chemical_compound MESH: Protein Structure Tertiary MESH: Protein Conformation Databases Protein [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] MESH: Allosteric Site MESH : Protein Conformation 0303 health sciences Multidisciplinary biology MESH : Bordetella pertussis MESH : Antigens Bacterial Biological Sciences MESH: Calmodulin MESH : Bacillus anthracis [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] Bacillus anthracis MESH: Bacillus anthracis Biochemistry MESH : Protein Structure Tertiary Allosteric Site MESH: Models Molecular MESH: Computational Biology MESH: Databases Protein MESH : Calmodulin Calmodulin MESH : Models Molecular Anthrax toxin Bacterial Toxins Allosteric regulation 010402 general chemistry drug discovery 03 medical and health sciences MESH: Chemistry Pharmaceutical Humans MESH : Databases Protein Binding site 030304 developmental biology Antigens Bacterial MESH: Humans MESH : Humans Computational Biology anthrax cyaA biology.organism_classification molecular dynamics Protein Structure Tertiary 0104 chemical sciences chemistry Allosteric enzyme MESH: Bacterial Toxins Drug Design transition path calculation MESH : Bacterial Toxins biology.protein MESH : Computational Biology MESH: Antigens Bacterial |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2010, 107 (25), pp.11277-11282. ⟨10.1073/pnas.0914611107⟩ Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2010, 107 (25), pp.11277-11282. 〈10.1073/pnas.0914611107〉 Proceedings of the National Academy of Sciences of the United States of America, 2010, 107 (25), pp.11277-11282. ⟨10.1073/pnas.0914611107⟩ |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.0914611107⟩ |
| Popis: | Allostery plays a key role in the regulation of the activity and function of many biomolecules. And although many ligands act through allostery, no systematic use is made of it in drug design strategies. Here we describe a procedure for identifying the regions of a protein that can be used to control its activity through allostery. This procedure is based on the construction of a plausible conformational path, which describes protein transition between known active and inactive conformations. The path is calculated by using a framework approach that steers and markedly improves the conjugate peak refinement method. The evolution of conformations along this path was used to identify a putative allosteric site that could regulate activation of Bacillus anthracis adenylyl cyclase toxin (EF) by calmodulin. Conformations of the allosteric site at different steps along the path from the inactive (free) to the active (bound to calmodulin) forms of EF were used to perform virtual screenings and propose candidate EF inhibitors. Several candidates then proved to inhibit calmodulin-induced activation in an in vitro assay. The most potent compound fully inhibited EF at a concentration of 10 μM. The compounds also inhibited the related adenylyl cyclase toxin from Bordetella pertussis (CyaA). The specific homology between the putative allosteric sites in both toxins supports that these pockets are the actual binding sites of the selected inhibitors. |
| Databáze: | OpenAIRE |
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