Molecular Dynamics Simulation on the Suppression Mechanism of Phosphorylation to Ser222 by Allosteric Inhibitors Targeting MEK1/2 Kinase.

ABSTRACT: Allosteric inhibitors of mitogen-activated protein kinase 1 (MEK1) reveal distinct interactions with MEK1 activation loop residues. The structural analyses will determine whether, and how, distinct inhibitors suppress the phosphorylation of MEK1 and may guide future therapeutic development. In this study, we explored the suppression mechanism of the phosphorylation process in the presence of MEK allosteric inhibitors, such as selumetinib, trametinib, cobimetinib, and CH5126766, by employing molecular dynamics simulations accompanied by principal component analysis. The simulations of wildtype MEK1 show that Ser222 can come close to γ-phosphate but not Ser218. We have found the conformation where Ser222 is within 5 Å of distance, which makes Ser222 accessible for γ-phosphate. The conformati

SUBMITTER: Mudedla SK 

PROVIDER: S-EPMC11270731 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature