2CHW: A Pharmacological Map Of The Pi3-K Family Defines A Role For P110 Alpha In Signaling: The Structure Of Complex Of Phosphoinositide 3-Kinase Gamma With Inhibitor Pik-39

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.
PDB ID: 2CHWDownload
MMDB ID: 39116
PDB Deposition Date: 2006/3/16
Updated in MMDB: 2011/10
Experimental Method:
x-ray diffraction
Resolution: 2.6  Å
Source Organism:
Similar Structures:
Biological Unit for 2CHW: monomeric; determined by author and by software (PQS)
Molecular Components in 2CHW
Label Count Molecule
Protein (1 molecule)
Phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Gamma Isoform(Gene symbol: PIK3CG)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB