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Use of allostery to identify inhibitors of calmodulin-induced activation of Bacillus anthracis edema factor.

TitleUse of allostery to identify inhibitors of calmodulin-induced activation of Bacillus anthracis edema factor.
Publication TypeJournal Article
Year of Publication2010
AuthorsLaine, E, Goncalves, C, Karst, JC, Lesnard, A, Rault, S, Tang, W-J, Malliavin, TE, Ladant, D, Blondel, A
JournalProc Natl Acad Sci U S A
Date Published2010 Jun 22
KeywordsAllosteric Site, Antigens, Bacterial, Bacillus anthracis, Bacterial Toxins, Bordetella pertussis, Calmodulin, Chemistry, Pharmaceutical, Computational Biology, Databases, Protein, Drug Design, Humans, Models, Molecular, Protein Conformation, Protein Structure, Tertiary

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 microM. 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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID20534570
PubMed Central IDPMC2895076

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