3D94

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

Summary for 3D94

• Entry DOI: 10.2210/pdb3d94/pdb
• Descriptor: 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)
• Functional Keywords: igf1rk, receptor tyrosine kinase, pqip, inhibitor, atp-binding, glycoprotein, membrane, nucleotide-binding, phosphoprotein, transferase, transmembrane, tyrosine-protein kinase
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein: P08069
• Total number of polymer chains: 1
• Total formula weight: 34978.27

Authors

Wu, J.,Li, W.,Miller, W.T.,Hubbard, S.R. (deposition date: 2008-05-26, release date: 2008-07-29, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.3 Å)