Allosteric activation via kinetic control: potassium accelerates a conformational change in IMP dehydrogenase.

ABSTRACT: Allosteric activators are generally believed to shift the equilibrium distribution of enzyme conformations to favor a catalytically productive structure; the kinetics of conformational exchange is seldom addressed. Several observations suggested that the usual allosteric mechanism might not apply to the activation of IMP dehydrogenase (IMPDH) by monovalent cations. Therefore, we investigated the mechanism of K(+) activation in IMPDH by delineating the kinetic mechanism in the absence of monovalent cations. Surprisingly, the K(+) dependence of k(cat) derives from the rate of flap closure, which increases by ≥65-fold in the presence of K(+). We performed both alchemical free energy simulations and potential of mean force calculations using the orthogonal space random walk strategy to computa

SUBMITTER: Riera TV 

PROVIDER: S-EPMC3186055 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature