2chx

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spinqualitylabelsall models 2chx, resolution 2.500Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

A PHARMACOLOGICAL MAP OF THE PI3-K FAMILY DEFINES A ROLE FOR P110ALPHA IN SIGNALING: THE STRUCTURE OF COMPLEX OF PHOSPHOINOSITIDE 3-KINASE GAMMA WITH INHIBITOR PIK-90

Overview

Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of, drug targets, but the unique roles of PI3-K isoforms remain poorly, defined. We describe here an approach to pharmacologically interrogate the, PI3-K family. A chemically diverse panel of PI3-K inhibitors was, synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal, structures of three inhibitors bound to p110gamma identify a, conformationally mobile region that is uniquely exploited by selective, compounds. This chemical array was then used to define the PI3-K isoforms, required for insulin signaling. We find that p110alpha is the primary, insulin-responsive PI3-K in cultured cells, whereas p110beta is, dispensable but sets a phenotypic threshold for p110alpha activity., Compounds targeting p110alpha block the acute effects of insulin treatment, in vivo, whereas a p110beta inhibitor has no effect. These results, illustrate systematic target validation using a matrix of inhibitors that, span a protein family.

About this Structure

2CHX is a Single protein structure of sequence from Homo sapiens with as ligand. Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling., Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM, Cell. 2006 May 19;125(4):733-47. Epub 2006 Apr 27. PMID:16647110

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