PDBsum entry 3dkg

Oncoprotein

PDB id: 3dkg

Contents

Protein chain

281 a.a. *

Ligands

SX8

Metals

_CL

Waters ×167

* Residue conservation analysis

PDB id:

3dkg

Name:

Oncoprotein

Title:

Structure of mutant(y1248l) met receptor tyrosine kinase in complex with inhibitor sgx-523

Structure:

Hepatocyte growth factor receptor. Chain: a. Synonym: hgf receptor, hgf/sf receptor, proto-oncogenE C-met, scatter factor receptor, sf receptor, tyrosine-protein kinase met. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: met, hcg_38705, tcag7.66. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

1.91Å R-factor: 0.195 R-free: 0.238

Authors:

J.Hendle

Key ref:

S.G.Buchanan et al. (2009). SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. Mol Cancer Ther, 8, 3181-3190. PubMed id: 19934279 DOI: 10.1158/1535-7163.MCT-09-0477

Date:

24-Jun-08 Release date: 07-Jul-09

Protein chain

P08581  (MET_HUMAN) -  Hepatocyte growth factor receptor from Homo sapiens

Seq: 1390 a.a.

Struc: 281 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1158/1535-7163.MCT-09-0477

Mol Cancer Ther 8:3181-3190 (2009)

PubMed id: 19934279

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo.

S.G.Buchanan, J.Hendle, P.S.Lee, C.R.Smith, P.Y.Bounaud, K.A.Jessen, C.M.Tang, N.H.Huser, J.D.Felce, K.J.Froning, M.C.Peterman, B.E.Aubol, S.F.Gessert, J.M.Sauder, K.D.Schwinn, M.Russell, I.A.Rooney, J.Adams, B.C.Leon, T.H.Do, J.M.Blaney, P.A.Sprengeler, D.A.Thompson, L.Smyth, L.A.Pelletier, S.Atwell, K.Holme, S.R.Wasserman, S.Emtage, S.K.Burley, S.H.Reich.

ABSTRACT

The MET receptor tyrosine kinase has emerged as an important target for the development of novel cancer therapeutics. Activation of MET by mutation or gene amplification has been linked to kidney, gastric, and lung cancers. In other cancers, such as glioblastoma, autocrine activation of MET has been demonstrated. Several classes of ATP-competitive inhibitor have been described, which inhibit MET but also other kinases. Here, we describe SGX523, a novel, ATP-competitive kinase inhibitor remarkable for its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC50 of 4 nmol/L and is >1,000-fold selective versus the >200-fold selectivity of other protein kinases tested in biochemical assays. Crystallographic study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity. SGX523 inhibited MET-mediated signaling, cell proliferation, and cell migration at nanomolar concentrations but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concentrations. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. Our results show that SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition.