1T45

STRUCTURAL BASIS FOR THE AUTOINHIBITION AND STI-571 INHIBITION OF C-KIT TYROSINE KINASE

1T45 の概要

• エントリーDOI: 10.2210/pdb1t45/pdb
• 関連するPDBエントリー: 1PKG 1t46
• 分子名称: Homo sapiens v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (2 entities in total)
• 機能のキーワード: kinase, autoinhibition, transferase activator
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37669.56

構造登録者

Mol, C.D.,Dougan, D.R.,Schneider, T.R.,Skene, R.J.,Kraus, M.L.,Scheibe, D.N.,Snell, G.P.,Zou, H.,Sang, B.C.,Wilson, K.P. (登録日: 2004-04-28, 公開日: 2004-06-15, 最終更新日: 2023-08-23)

主引用文献

Mol, C.D.,Dougan, D.R.,Schneider, T.R.,Skene, R.J.,Kraus, M.L.,Scheibe, D.N.,Snell, G.P.,Zou, H.,Sang, B.C.,Wilson, K.P.
Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase.
J.Biol.Chem., 279:31655-31663, 2004

PubMed Abstract: The activity of the c-Kit receptor protein-tyrosine kinase is tightly regulated in normal cells, whereas deregulated c-Kit kinase activity is implicated in the pathogenesis of human cancers. The c-Kit juxtamembrane region is known to have an autoinhibitory function; however the precise mechanism by which c-Kit is maintained in an autoinhibited state is not known. We report the 1.9-A resolution crystal structure of native c-Kit kinase in an autoinhibited conformation and compare it with active c-Kit kinase. Autoinhibited c-Kit is stabilized by the juxtamembrane domain, which inserts into the kinase-active site and disrupts formation of the activated structure. A 1.6-A crystal structure of c-Kit in complex with STI-571 (Imatinib or Gleevec) demonstrates that inhibitor binding disrupts this natural mechanism for maintaining c-Kit in an autoinhibited state. Together, these results provide a structural basis for understanding c-Kit kinase autoinhibition and will facilitate the structure-guided design of specific inhibitors that target the activated and autoinhibited conformations of c-Kit kinase.

PubMed: 15123710
DOI: 10.1074/jbc.M403319200

実験手法

X-RAY DIFFRACTION (1.9 Å)