Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor
important in diverse biological processes including cell proliferation
and survival. Upregulation of EGFR activity due to over-expression or
mutation is widely implicated in cancer. Activating somatic mutations of
the EGFR kinase are postulated to affect the conformation and/or
stability of the protein, shifting the EGFR inactive-active state
equilibrium towards the activated state. Here, we examined a common EGFR
deletion mutation, Δ⁷⁴⁶ELREA⁷⁵⁰, which is
frequently observed in non-small cell lung cancer patients. By using
molecular dynamics simulation, we investigated the structural effects of
the mutation that lead to the experimentally reported increases in
kinase activity. Simulations of the active form wild-type and ΔELREA
EGFRs revealed the deletion stabilizes the αC helix of the kinase
domain, which is located adjacent to the deletion site, by rigidifying
the flexible β3-αC loop that accommodates the ELREA sequence.
Consequently, the αC helix is stabilized in the “αC-in” active
conformation that would prolong the time of the activated state.
Moreover, in the mutant kinase, a salt bridge between E762 and K745,
which is key for EGFR activity, was also stabilized during the
simulation. Additionally, the interaction between EGFR and ATP was
favored by ΔELREA EGFR over wild-type EGFR, as reflected by the number
of hydrogen bonds formed and the free energy of binding. Simulation of
inactive EGFR suggested the deletion would promote a shift from the
inactive conformation towards active EGFR, which is supported by the
inward movement of the αC helix. The MDS results also align with the
effects of tyrosine kinase inhibitors on ΔELREA and wild-type EGFR lung
cancer cell lines, where more pronounced inhibition was observed against
ΔELREA than for wild-type EGFR by inhibitors recognizing the active
kinase conformation.