Structural characterization of EGFR exon 19 deletion mutation using molecular dynamics simulation


Autoři: Mahlet Z. Tamirat aff001;  Marika Koivu aff002;  Klaus Elenius aff002;  Mark S. Johnson aff001
Působiště autorů: Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland aff001;  Medicity Research Laboratories and Institute of Biomedicine, University of Turku, Turku, Finland aff002;  Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland aff003;  Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland aff004;  Department of Oncology and Radiotherapy, University of Turku and Turku University Hospital, Turku, Finland aff005
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pone.0222814

Souhrn

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.

Klíčová slova:

Biology and life sciences – Biochemistry – Enzymology – Enzymes – Protein kinases – Tyrosine kinases – Proteins – Salt bridges – Genetics – Mutation – Deletion mutation – Somatic mutation – Computational biology – Physical sciences – Chemistry – Electrochemistry – Physical chemistry – Chemical bonding – Hydrogen bonding – Computational chemistry – Molecular dynamics – Physics – Thermodynamics – Free energy – Biophysics – Biophysical simulations


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