Structural Basis for the Functional Changes by EGFR Exon 20 Insertion Mutations.

ABSTRACT: Activating somatic mutations of the epidermal growth factor receptor (EGFR) are frequently implicated in non-small cell lung cancer (NSCLC). While L858R and exon 19 deletion mutations are most prevalent, exon 20 insertions are often observed in NSCLC. Here, we investigated the structural implications of two common EGFR exon 20 insertions in NSCLC, V769insASV and D770insNPG. The active and inactive conformations of wild-type, D770insNPG and V769insASV EGFRs were probed with molecular dynamics simulations to identify local and global alterations that the mutations exert on the EGFR kinase domain, highlighting mechanisms for increased enzymatic activity. In the active conformation, the mutations increase interactions that stabilize the αC helix that is essential for EGFR activity. Moreover, t

SUBMITTER: Tamirat MZ 

PROVIDER: S-EPMC7961794 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature