1T46

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

Summary for 1T46

• Entry DOI: 10.2210/pdb1t46/pdb
• Related: 1PKG 1T45
• Descriptor: Homo sapiens v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, PHOSPHATE ION, 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE, ... (4 entities in total)
• Functional Keywords: kinase, inhibitor, sti-571, gleevec, transferase activator
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 36072.48

Authors

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. (deposition date: 2004-04-28, release date: 2004-06-15, Last modification date: 2024-02-14)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.6 Å)