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Gatekeeper mutations activate FGF receptor tyrosine kinases by destabilizing the autoinhibited state

Alida Besch1, William M Marsiglia1, Moosa Mohammadi2

  • 1Department of Chemistry, New York University, New York, NY 10003.

Proceedings of the National Academy of Sciences of the United States of America
|February 15, 2023
PubMed

Insights

Gatekeeper mutations in tyrosine kinases, often found in cancer drug resistance, boost kinase activity. These mutations destabilize the kinase, promoting its active state and leading to more aggressive cancers.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Small molecule ATP-competitive inhibitors target receptor tyrosine kinases for cancer treatment.
  • Gatekeeper mutations in tyrosine kinases confer drug resistance and increase cancer aggressiveness.
  • The gain-of-function mechanism of gatekeeper mutations remains poorly understood.

Purpose of the Study:

  • To investigate the mechanism by which gatekeeper mutations in fibroblast growth factor receptor (FGFR) tyrosine kinases lead to enhanced activity.
  • To elucidate how these mutations contribute to cancer progression and drug resistance.

Main Methods:

  • Kinase activity assays
  • Nuclear Magnetic Resonance (NMR) spectroscopy
  • Bioinformatic analyses
  • Molecular Dynamics (MD) simulations

Main Results:

  • Gatekeeper mutations were found to destabilize the autoinhibitory conformation of the DFG motif.
  • These mutations globally destabilize the tyrosine kinase domain.
  • The destabilization facilitates the kinase's transition to and population of the active state.

Conclusions:

  • Gatekeeper mutations confer gain-of-function by promoting the active conformation of tyrosine kinases.
  • Understanding this mechanism is crucial for developing strategies to overcome drug resistance in cancer therapy.
Keywords:
NMR spectroscopymolecular dynamicsreceptor tyrosine kinases

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