National Academy of Sciences, Proceedings of the National Academy of Sciences, 20(116), p. 10009-10018, 2019
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Significance EGFR cancer mutations display an astonishing tissue-specific asymmetry: in lung cancer, mutations target the intracellular kinase (KD), while in glioblastomas (GBMs), a variety of missense clusters and deletions concentrate at the ectodomain (ECD). Intriguingly, GBM-activating mutations share a paradoxical preference for inhibitors that bind the inactive kinase. By integrating simulations, small-angle X-ray scattering, and GBM models, we demonstrate that ECD mutants converge to a transition state characterized by a cryptic epitope, allosterically coupled to an intermediate kinase, and synergistically blocked by antibodies and inhibitors. Our findings indicate that apparently heterogeneous aberrations remove a similar steric restrain on KD activation. The diversity of structural tricks in ECD mutants to achieve the same conformational state constitutes a potent example of molecular mimicry and convergence.