The Traaseth and Zhang Labs reported that “gatekeeper” mutations make enzymes called kinases more active by destabilizing them in their inactive form, which may explain more aggressive cancer recurrence. The study, entitled "Gatekeeper Mutations Activate FGF Receptor Tyrosine Kinases by Destabilizing the Autoinhibited State," was published in the Proceedings of the National Academy of Sciences (PNAS). The first author is doctoral student Alida Besch, and other NYU Chemistry contributors are alumnus William Marsiglia (currently at the University of Alabama Birmingham) and Professors Nate Traaseth and Yingkai Zhang.
Click here to read the full article in PNAS:
Click here to read the NYU research press release:
Abstract: 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 FGF receptor tyrosine kinases harboring two distinct gatekeeper mutations using kinase activity assays, NMR spectroscopy, bioinformatic analyses, and MD simulations. We show that gatekeeper mutations destabilize the autoinhibited state and lead to conformational changes at the DFG motif, suggesting an activation model where mutations shift the equilibrium to the active state of the kinase.
This research was supported by the National Institutes of Health and the National Science Foundation.