Structural Basis for the Autoinhibition and STI-571 Inhibition of c-Kit Tyrosine Kinase
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...
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Veröffentlicht in: | The Journal of biological chemistry 2004-07, Vol.279 (30), p.31655-31663 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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-Ã
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-Ã
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. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M403319200 |