Epidermal growth factor receptor kinase is implicated in cancer development due to either overexpression or activation variants in its functional intracellular kinase domain. Threonine to methionine (Thr 790 Met) is one such variant observed commonly in patients showing resistance to kinase inhibitor drug Erlotinib. Two mechanisms for resistance have been proposed (1) steric hindrance and (2) enhanced binding to ATP. In this study, we employed molecular dynamics simulations and studied both the mechanisms. Extensive simulations and free energy of binding analyses has shown that steric hindrance does not explain appropriately the mechanism for resistance against Erlotinib therapy for this variant. It has been observed that conformational switching from an intermediate intrinsically disordered C-helix conformation is required for completion of the kinase's catalytic cycle. Our study substantiates that T790M variant has greater tendency for early transition to this intrinsically disordered C-helix intermediate state. We propose that enhanced catalytic efficiency in addition to enhanced ATP binding explains mechanism of T790M resistance to drug Erlotinib.
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