Molecular motions as a drug target: mechanistic simulations of anthrax toxin edema factor function led to the discovery of novel allosteric inhibitors.

ABSTRACT: Edema Factor (EF) is a component of Bacillus anthracis toxin essential for virulence. Its adenylyl cyclase activity is induced by complexation with the ubiquitous eukaryotic cellular protein, calmodulin (CaM). EF and its complexes with CaM, nucleotides and/or ions, have been extensively characterized by X-ray crystallography. Those structural data allowed molecular simulations analysis of various aspects of EF action mechanism, including the delineation of EF and CaM domains through their association energetics, the impact of calcium binding on CaM, and the role of catalytic site ions. Furthermore, a transition path connecting the free inactive form to the CaM-complexed active form of EF was built to model the activation mechanism in an attempt to define an inhibition strategy. The cavitie

SUBMITTER: Laine E 

PROVIDER: S-EPMC3446745 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature