Electrostatic mechanism of V600E mutation-induced B-Raf constitutive activation in colorectal cancer: molecular implications for the selectivity difference between type-I and type-II inhibitors

European Biophysics Journal : EBJ
Tie LiuNa Ding

Abstract

The oncogenic mutation V600E in B-Raf activation loop (A-loop) has been frequently observed to cause drug resistance in colorectal cancer chemotherapy. Here, the molecular mechanism of V600E-induced conformational flipping of B-Raf activation loop (A-loop) is investigated systematically via continuum electrostatic analysis. It is found that substitution of the electroneutral Val600 residue with negatively charged glutamic acid Glu600 electrostatically destabilizes the inactive DFG-out conformation of B-Raf kinase and promotes its shifting to active DFG-in conformation. This is analogous with natural phosphorylation of Thr598 and/or Ser601 residues in A-loop to activate the kinase, that is, both the mutation and phosphorylation can introduce negative charge to B-Raf A-loop and then trigger the loop flipping. Energetic analysis reveals that the V600E mutation can affect inhibitor binding indirectly via regulation of kinase conformation. Type-I and type-II inhibitors respond distinctly to V600E mutation; the former is sensitized by the mutation, while the latter generally shows a low sensitivity to the mutation. Based on this guideline, the sophisticated type-I pan-kinase inhibitor Staurosporine as well as its analogs Midostaurin ...Continue Reading

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Citations

Sep 9, 2020·Journal of Biomolecular Structure & Dynamics·Gregory A BabbittAndré O Hudson
Jun 1, 2021·Signal Transduction and Targeted Therapy·Lei ZhongShengyong Yang

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