2RFN

x-ray structure of c-Met with inhibitor.

2RFN の概要

• エントリーDOI: 10.2210/pdb2rfn/pdb
• 関連するPDBエントリー: 2RFS
• 分子名称: Hepatocyte growth factor receptor, 2-benzyl-5-(3-fluoro-4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxy}phenyl)-3-methylpyrimidin-4(3H)-one (3 entities in total)
• 機能のキーワード: c-met hgf receptor tyrosine kinse kinase domain, atp-binding, glycoprotein, membrane, nucleotide-binding, phosphorylation, proto-oncogene, 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: P08581
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 71915.17

構造登録者

Bellon, S.F.,Kaplan-Lefko, P.,Yang, Y.,Zhang, Y.,Moriguchi, J.,Dussault, I. (登録日: 2007-10-01, 公開日: 2007-11-06, 最終更新日: 2023-08-30)

主引用文献

Bellon, S.F.,Kaplan-Lefko, P.,Yang, Y.,Zhang, Y.,Moriguchi, J.,Rex, K.,Johnson, C.W.,Rose, P.E.,Long, A.M.,O'Connor, A.B.,Gu, Y.,Coxon, A.,Kim, T.S.,Tasker, A.,Burgess, T.L.,Dussault, I.
c-Met inhibitors with novel binding mode show activity against several hereditary papillary renal cell carcinoma-related mutations.
J.Biol.Chem., 283:2675-2683, 2008

PubMed Abstract: c-Met is a receptor tyrosine kinase often deregulated in human cancers, thus making it an attractive drug target. One mechanism by which c-Met deregulation leads to cancer is through gain-of-function mutations. Therefore, small molecules capable of targeting these mutations could offer therapeutic benefits for affected patients. SU11274 was recently described and reported to inhibit the activity of the wild-type and some mutant forms of c-Met, whereas other mutants are resistant to inhibition. We identified a novel series of c-Met small molecule inhibitors that are active against multiple mutants previously identified in hereditary papillary renal cell carcinoma patients. AM7 is active against wild-type c-Met as well as several mutants, inhibits c-Met-mediated signaling in MKN-45 and U-87 MG cells, and inhibits tumor growth in these two models grown as xenografts. The crystal structures of AM7 and SU11274 bound to unphosphorylated c-Met have been determined. The AM7 structure reveals a novel binding mode compared with other published c-Met inhibitors and SU11274. The molecule binds the kinase linker and then extends into a new hydrophobic binding site. This binding site is created by a significant movement of the C-helix and so represents an inactive conformation of the c-Met kinase. Thus, our results demonstrate that it is possible to identify and design inhibitors that will likely be active against mutants found in different cancers.

PubMed: 18055465
DOI: 10.1074/jbc.M705774200

実験手法

X-RAY DIFFRACTION (2.5 Å)