Structural comparisons of class I phosphoinositide 3-kinases

Abstract

The recent determination of the structure of the class I phosphoinositide 3-kinase PI3Kα has identified important structural differences between the class 1 PI3Ks. How can this information be used to improve cancer therapy? Class I phosphoinositide 3-kinases (PI3Ks) are lipid kinases that regulate cell growth. One of these kinases, PI3Kα, is frequently mutated in diverse tumour types. The recently determined structure of PI3Kα reveals features that distinguish this enzyme from related lipid kinases. In addition, wild-type PI3Kγ differs from PI3Kα by a substitution identical to a PI3Kα oncogenic mutant (His1047Arg) that might explain the differences in the enzymatic activities of the normal and mutant PI3Kα. Comparison of the PI3K structures also identified structural features that could potentially be exploited for the design of isoform-specific inhibitors.