Capitalizing on tumor genotyping: towards the design of mutation specific inhibitors of phosphoinsitide-3-kinase.

ABSTRACT: PI3Ks catalyze the phosphorylation of the inositol hydroxyls of phosphoinositide membrane components. The changes in phosphorylation of the inositides recruit proteins to the plasma membrane that initiate important signaling cascades. PI3Kα, one of the class IA PI3Ks, is highly mutated in cancers. All mutations analyzed result in an increase in enzymatic activity. The structures of this enzyme determined by X-ray diffraction, provide a framework for analyzing the possible structural effect of these mutations and their effect on the enzymatic activity. Many of the mutations occur at domain interfaces where they can affect domain interactions and relieve the inhibition of the wild-type enzyme by the nSH2 domain of p85. This mechanism is analogous to the mechanism of physiological activation

SUBMITTER: Gabelli SB 

PROVIDER: S-EPMC3079044 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature