2WXN

The crystal structure of the murine class IA PI 3-kinase p110delta in complex with DL07.

2WXN の概要

• エントリーDOI: 10.2210/pdb2wxn/pdb
• 関連するPDBエントリー: 2WXE 2WXF 2WXG 2WXH 2WXI 2WXJ 2WXK 2WXL 2WXM 2WXO 2WXP 2WXQ 2WXR
• 分子名称: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT DELTA ISOFORM, 3-{[4-amino-1-(1-methylethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]ethynyl}phenol (3 entities in total)
• 機能のキーワード: transferase, phosphoprotein, isoform-specific inhibitors, cancer
• 由来する生物種: MUS MUSCULUS (HOUSE MOUSE)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 108116.99

構造登録者

Berndt, A.,Miller, S.,Williams, O.,Lee, D.D.,Houseman, B.T.,Pacold, J.I.,Gorrec, F.,Hon, W.-C.,Liu, Y.,Rommel, C.,Gaillard, P.,Ruckle, T.,Schwarz, M.K.,Shokat, K.M.,Shaw, J.P.,Williams, R.L. (登録日: 2009-11-09, 公開日: 2010-01-12, 最終更新日: 2023-12-20)

主引用文献

Berndt, A.,Miller, S.,Williams, O.,Lee, D.D.,Houseman, B.T.,Pacold, J.I.,Gorrec, F.,Hon, W.-C.,Liu, Y.,Rommel, C.,Gaillard, P.,Ruckle, T.,Schwarz, M.K.,Shokat, K.M.,Shaw, J.P.,Williams, R.L.
The P110D Structure: Mechanisms for Selectivity and Potency of New Pi(3)K Inhibitors
Nat.Chem.Biol., 6:117-, 2010

PubMed Abstract: Deregulation of the phosphoinositide-3-OH kinase (PI(3)K) pathway has been implicated in numerous pathologies including cancer, diabetes, thrombosis, rheumatoid arthritis and asthma. Recently, small-molecule and ATP-competitive PI(3)K inhibitors with a wide range of selectivities have entered clinical development. In order to understand the mechanisms underlying the isoform selectivity of these inhibitors, we developed a new expression strategy that enabled us to determine to our knowledge the first crystal structure of the catalytic subunit of the class IA PI(3)K p110 delta. Structures of this enzyme in complex with a broad panel of isoform- and pan-selective class I PI(3)K inhibitors reveal that selectivity toward p110 delta can be achieved by exploiting its conformational flexibility and the sequence diversity of active site residues that do not contact ATP. We have used these observations to rationalize and synthesize highly selective inhibitors for p110 delta with greatly improved potencies.

PubMed: 20081827
DOI: 10.1038/NCHEMBIO.293

実験手法

X-RAY DIFFRACTION (2.6 Å)