1TVO

The structure of ERK2 in complex with a small molecule inhibitor

1TVO の概要

• エントリーDOI: 10.2210/pdb1tvo/pdb
• 分子名称: Mitogen-activated protein kinase 1, 5-(2-PHENYLPYRAZOLO[1,5-A]PYRIDIN-3-YL)-1H-PYRAZOLO[3,4-C]PYRIDAZIN-3-AMINE (3 entities in total)
• 機能のキーワード: kinase, protein-inhibitor complex, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton, spindle : P28482
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42558.78

構造登録者

Kinoshita, T. (登録日: 2004-06-30, 公開日: 2005-09-13, 最終更新日: 2024-03-13)

主引用文献

Ohori, M.,Kinoshita, T.,Okubo, M.,Sato, K.,Yamazaki, A.,Arakawa, H.,Nishimura, S.,Inamura, N.,Nakajima, H.,Neya, M.,Miyake, H.,Fujii, T.
Identification of a selective ERK inhibitor and structural determination of the inhibitor-ERK2 complex
Biochem.Biophys.Res.Commun., 336:357-363, 2005

PubMed Abstract: 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.

PubMed: 16139248
DOI: 10.1016/j.bbrc.2005.08.082

実験手法

X-RAY DIFFRACTION (2.5 Å)