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Title: Gatekeeper mutations activate FGF receptor tyrosine kinases by destabilizing the autoinhibited state
Many types of human cancers are being treated with small molecule ATP-competitive inhibitors targeting the kinase domain of receptor tyrosine kinases. Despite initial successful remission, long-term treatment almost inevitably leads to the emergence of drug resistance mutations at the gatekeeper residue hindering the access of the inhibitor to a hydrophobic pocket at the back of the ATP-binding cleft. In addition to reducing drug efficacy, gatekeeper mutations elevate the intrinsic activity of the tyrosine kinase domain leading to more aggressive types of cancer. However, the mechanism of gain-of-function by gatekeeper mutations is poorly understood. Here, we characterized fibroblast growth factor receptor (FGFR) tyrosine kinases harboring two distinct gatekeeper mutations using kinase activity assays, NMR spectroscopy, bioinformatic analyses, and MD simulations. Our data show that gatekeeper mutations destabilize the autoinhibitory conformation of the DFG motif locally and of the kinase globally, suggesting they impart gain-of-function by facilitating the kinase's ability to populate the active state.  more » « less
Award ID(s):
1902449
PAR ID:
10443612
Author(s) / Creator(s):
; ; ; ;
Date Published:
Journal Name:
Proceedings of the National Academy of Sciences
Volume:
120
Issue:
8
ISSN:
0027-8424
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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