3RHK

Crystal structure of the catalytic domain of c-Met kinase in complex with ARQ 197

Summary for 3RHK

• Entry DOI: 10.2210/pdb3rhk/pdb
• Descriptor: Hepatocyte growth factor receptor, 1-[(3R,4R)-4-(1H-indol-3-yl)-2,5-dioxopyrrolidin-3-yl]pyrrolo[3,2,1-ij]quinolinium (3 entities in total)
• Functional Keywords: kinase, receptor tyrosine kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P08581
• Total number of polymer chains: 2
• Total formula weight: 72714.05

Authors

Eathiraj, S.,Palma, R.,Volckova, E.,Hirschi, M.,France, D.S.,Ashwell, M.A.,Chan, T.C. (deposition date: 2011-04-11, release date: 2011-04-27, Last modification date: 2024-02-21)

Primary citation

Eathiraj, S.,Palma, R.,Volckova, E.,Hirschi, M.,France, D.S.,Ashwell, M.A.,Chan, T.C.
Discovery of a novel mode of protein kinase inhibition characterized by the mechanism of inhibition of human mesenchymal-epithelial transition factor (c-Met) protein autophosphorylation by ARQ 197.
J.Biol.Chem., 286:20666-20676, 2011

PubMed Abstract: A number of human malignancies exhibit sustained stimulation, mutation, or gene amplification of the receptor tyrosine kinase human mesenchymal-epithelial transition factor (c-Met). ARQ 197 is a clinically advanced, selective, orally bioavailable, and well tolerated c-Met inhibitor, currently in Phase 3 clinical testing in non-small cell lung cancer patients. Herein, we describe the molecular and structural basis by which ARQ 197 selectively targets c-Met. Through our analysis we reveal a previously undisclosed, novel inhibitory mechanism that utilizes distinct regulatory elements of the c-Met kinase. The structure of ARQ 197 in complex with the c-Met kinase domain shows that the inhibitor binds a conformation that is distinct from published kinase structures. ARQ 197 inhibits c-Met autophosphorylation and is highly selective for the inactive or unphosphorylated form of c-Met. Through our analysis of the interplay between the regulatory and catalytic residues of c-Met, and by comparison between the autoinhibited canonical conformation of c-Met bound by ARQ 197 to previously described kinase domains of type III receptor tyrosine kinases, we believe this to be the basis of a powerful new in silico approach for the design of similar inhibitors for other protein kinases of therapeutic interest.

PubMed: 21454604
DOI: 10.1074/jbc.M110.213801

Experimental method

X-RAY DIFFRACTION (1.94 Å)