3D94

Crystal structure of the insulin-like growth factor-1 receptor kinase in complex with PQIP

3D94 の概要

• エントリーDOI: 10.2210/pdb3d94/pdb
• 分子名称: Insulin-like growth factor 1 receptor beta chain, CALCIUM ION, 3-[cis-3-(4-methylpiperazin-1-yl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine, ... (4 entities in total)
• 機能のキーワード: igf1rk, receptor tyrosine kinase, pqip, inhibitor, atp-binding, glycoprotein, membrane, nucleotide-binding, phosphoprotein, transferase, transmembrane, tyrosine-protein kinase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P08069
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34978.27

構造登録者

Wu, J.,Li, W.,Miller, W.T.,Hubbard, S.R. (登録日: 2008-05-26, 公開日: 2008-07-29, 最終更新日: 2024-10-30)

主引用文献

Wu, J.,Li, W.,Craddock, B.P.,Foreman, K.W.,Mulvihill, M.J.,Ji, Q.S.,Miller, W.T.,Hubbard, S.R.
Small-molecule inhibition and activation-loop trans-phosphorylation of the IGF1 receptor
Embo J., 27:1985-1994, 2008

PubMed Abstract: The insulin-like growth factor-1 receptor (IGF1R) is a receptor tyrosine kinase (RTK) that has a critical role in mitogenic signalling during embryogenesis and an antiapoptotic role in the survival and progression of many human tumours. Here, we present the crystal structure of the tyrosine kinase domain of IGF1R (IGF1RK), in its unphosphorylated state, in complex with a novel compound, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which we show is a potent inhibitor of both the unphosphorylated (basal) and phosphorylated (activated) states of the kinase. PQIP interacts with residues in the ATP-binding pocket and in the activation loop, which confers specificity for IGF1RK and the highly related insulin receptor (IR) kinase. In this crystal structure, the IGF1RK active site is occupied by Tyr1135 from the activation loop of an symmetry (two-fold)-related molecule. This dimeric arrangement affords, for the first time, a visualization of the initial trans-phosphorylation event in the activation loop of an RTK, and provides a molecular rationale for a naturally occurring mutation in the activation loop of the IR that causes type II diabetes mellitus.

PubMed: 18566589
DOI: 10.1038/emboj.2008.116

実験手法

X-RAY DIFFRACTION (2.3 Å)