Structural Basis for the Autoinhibition and STI-571 Inhibition of c-Kit Tyrosine Kinase*
By C. Mol, D. Dougan, Thomas R. Schneider, R. Skene, M. Kraus, D. Scheibe, G. Snell, Hua Zou, Biching Sang, K. Wilson. Journal of Biological Chemistry, 2004
621 citations recorded by the source corpus.
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-Å 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-Å 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.
Subfields: Genetics, Pathology and Forensic Medicine
View Paper: https://www.semanticscholar.org/paper/5acd4c6a15d5634bc61c88528162be00ee74a523
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In Genetics
Citations in the corpus
- Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. (2006, background): “The imatinib-resistant tumors contained abundant amounts of activated KIT.”
- Gastrointestinal stromal tumours: origin and molecular oncology (2011, background): “Two-thirds of GISTs harbour mutations in exon 11, which disrupt the normal juxtamembrane secondary structure that prevents the kinase activation loop from swinging into the active conformatio”
- Mechanisms of receptor tyrosine kinase activation in cancer (2018, positive): “KIT and Eph receptors are regulated by juxtamembrane autoinhibition, in which the juxtamembrane region interacts with components within the active site of the kinase—thereby stabilizing an inactive state [20, 23].”
- The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. (2006, background): “Some native kinases, such as KIT, exist in an autoinhibitory state due to the activation loop inserting into the kinase active site, thus disrupting formation of the activated structure (38).”