KRAS(G12C)-AMG 510 interaction dynamics revealed by all-atom molecular dynamics simulations.

Scientific Reports
Tatu Pantsar

Abstract

The first KRAS(G12C) targeting inhibitor in clinical development, AMG 510, has shown promising antitumor activity in clinical trials. On the molecular level, however, the interaction dynamics of this covalently bound drug-protein complex has been undetermined. Here, we disclose the interaction dynamics of the KRAS(G12C)-AMG 510 complex by long timescale all-atom molecular dynamics (MD) simulations (total of 75 μs). Moreover, we investigated the influence of the recently reported post-translational modification (PTM) of KRAS' N-terminus, removal of initiator methionine (iMet1) with acetylation of Thr2, to this complex. Our results demonstrate that AMG 510 does not entrap KRAS into a single conformation, as one would expect based on the crystal structure, but rather into an ensemble of conformations. AMG 510 binding is extremely stable regardless of highly dynamic interface of KRAS' switches. Overall, KRAS(G12C)-AMG 510 complex partially mimic the native dynamics of GDP bound KRAS; however, AMG 510 stabilizes the α3-helix region. N-terminally modified KRAS displays similar interaction dynamics with AMG 510 as when Met1 is present, but this PTM appears to stabilize β2-β3-loop. These results provide novel conformational insights on...Continue Reading

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Citations

Dec 22, 2020·Biophysical Journal·Nurit HaspelRuth Nussinov
May 11, 2021·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Takamasa KogaTetsuya Mitsudomi
Aug 22, 2021·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Colin R LindsayJulien Mazières

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Methods Mentioned

BETA
acetylation
nucleotide exchange
NMR

Clinical Trials Mentioned

NCT03600883
NCT04185883
NCT03785249
NCT04006301
NCT04165031

Software Mentioned

PCCA
RESPA
Maestro
Protein preparation wizard
OPLS3e

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