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Analyse de l'activation du facteur oedémateux de Bacillus anthracis par la calmoduline, en vue de la recherche d'inhibiteurs

Abstract : The virulence of the Gram+ bacterium Bacillus anthracis, responsible for anthrax disease, is caused by a capsule and two toxins. Each toxin is formed from the assembly of the protective antigen (PA) and either the lethal factor (LF) or the edema factor (EF) in the cytoplasm of host cells. EF is an adenylate cyclase, that produces cAMP from ATP in an uncontrolled fashion, provoking severe cellular dysfunction. EF is activated by calmodulin (CaM), involved in many calcium signaling pathways. Crystallographic structures and an NMR study showed that the level of calcium bound to CaM inuences the stability of the EF-CaM complex. Molecular dynamics simulations of the complex, with 0, 2 or 4 calcium ions, enabled to characterize the effect of calcium on the conformational plasticity of each partner and to propose a model for the EF-CaM interaction. The joint analysis of dynamical correlations and energetic influences raised the concept of residue network connectedness as a stability criterion. The large conformational transition undergone by EF upon CaM binding was described through the determination of a plausible reaction path. The obtained intermediate conformations were further used to guide the rational search for inhibitors of the EF toxin, in an approach combining computational and experimental methods. An innovative strategy involving the virtual screening of an allosteric pocket instead of the catalytic site of the enzyme, identified six active compounds able to fully inhibit EF activity at concentrations of 10-100 μM.
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https://tel.archives-ouvertes.fr/tel-00483602
Contributor : Elodie Laine <>
Submitted on : Friday, May 14, 2010 - 6:30:16 PM
Last modification on : Monday, December 14, 2020 - 9:55:41 AM
Long-term archiving on: : Thursday, September 16, 2010 - 1:54:49 PM

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  • HAL Id : tel-00483602, version 1

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Elodie Laine. Analyse de l'activation du facteur oedémateux de Bacillus anthracis par la calmoduline, en vue de la recherche d'inhibiteurs. Médicaments. Université Pierre et Marie Curie - Paris VI, 2009. Français. ⟨tel-00483602⟩

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