1tvo
From Proteopedia
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The structure of ERK2 in complex with a small molecule inhibitor
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Overview
Selective inhibition of extracellular signal-regulated kinase (ERK), represents a potential approach for the treatment of cancer and other, diseases; however, no selective inhibitors are currently available. Here, we describe an ERK-selective inhibitor, FR180204, and determine the, structural basis of its selectivity. FR180204 inhibited the kinase, activity of ERK1 and ERK2, with K(i) values 0.31 and 0.14microM, respectively. Lineweaver-Burk analysis of the binding interaction revealed, that FR180204 acted as competitive inhibitor of ATP. In mink lung, epithelial Mv1Lu cells, FR180204 inhibited TGFbeta-induced, luciferase-expression. X-ray crystal structure analysis of the human, ERK2/FR180204 complex revealed that Q105, D106, L156, and C166, which form, the ATP-binding pocket on ERK, play important roles in the drug/protein, interaction. These results suggest that FR180204 is an ERK-selective and, cell-permeable inhibitor, and could be useful for elucidating the roles of, ERK as well as for drug development.
Disease
Known diseases associated with this structure: Epileptic encephalopathy, Lennox-Gastaut type OMIM:[602897]
About this Structure
1TVO is a Single protein structure of sequence from Homo sapiens with FRZ as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
Reference
Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex., Ohori M, Kinoshita T, Okubo M, Sato K, Yamazaki A, Arakawa H, Nishimura S, Inamura N, Nakajima H, Neya M, Miyake H, Fujii T, Biochem Biophys Res Commun. 2005 Oct 14;336(1):357-63. PMID:16139248
Page seeded by OCA on Mon Nov 12 19:28:36 2007
