2CHX

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

2CHX の概要

• エントリーDOI: 10.2210/pdb2chx/pdb
• 関連するPDBエントリー: 1E8Y 1E8Z 1HE8 2A4Z 2A5U 2CHW 2CHZ
• 分子名称: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM, N-(2,3-DIHYDRO-7,8-DIMETHOXYIMIDAZO[1,2-C] QUINAZOLIN-5-YL)NICOTINAMIDE (2 entities in total)
• 機能のキーワード: phosphoinositide, kinase, lipid, inhibitor, 3-kinase, signaling, quinazolinone, transferase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 111106.51

構造登録者

Knight, Z.A.,Gonzalez, B.,Feldman, M.E.,Zunder, E.R.,Goldenberg, D.D.,Williams, O.,Loewith, R.,Stokoe, D.,Balla, A.,Toth, B.,Balla, T.,Weiss, W.A.,Williams, R.L.,Shokat, K.M. (登録日: 2006-03-16, 公開日: 2006-05-22, 最終更新日: 2023-12-13)

主引用文献

Knight, Z.A.,Gonzalez, B.,Feldman, M.E.,Zunder, E.R.,Goldenberg, D.D.,Williams, O.,Loewith, R.,Stokoe, D.,Balla, A.,Toth, B.,Balla, T.,Weiss, W.A.,Williams, R.L.,Shokat, K.M.
A Pharmacological Map of the Pi3-K Family Defines a Role for P110Alpha in Signaling
Cell(Cambridge,Mass.), 125:733-, 2006

PubMed Abstract: 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.

PubMed: 16647110
DOI: 10.1016/J.CELL.2006.03.035

実験手法

X-RAY DIFFRACTION (2.5 Å)