How oncogenic mutations activate human MAP kinase 1 (MEK1): a molecular dynamics simulation study. Issue 13 (1st September 2020)

• Record Type: Journal Article
• Authors: Liu, Ye; Zhu, Jingxuan; Guo, Xiaoqing; Huang, Tianci; Han, Jiarui; Gao, Jianjiong; Xu, Dong; Han, Weiwei
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 38:Issue 13(2020)
• Page Start: 3942
• Page End: 3958
• Publication Date: 2020-09-01
• Subjects: MAP kinase 1 (MEK1) -- MAPK pathway -- cancer -- molecular dynamics simulation -- MM-PBSA -- conformational change; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2019.1686065
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: Approximately 30% of all types of human cancers possess a constitutively activated the mitogen-activated protein kinase (MAPK) signaling pathway while MAP kinase 1 (MEK1) is a critical component of this pathway. It has been reported mutations could improve the activity of MEK1 to result in cell proliferation and transformation, which is a known oncogenic event in various cancer types. In this study, eight molecular dynamics simulations, molecular mechanics Poisson–Boltzmann surface area (MM-PBSA), combined with protein structure network were performed to explore the mechanism that mutations activate MEK1. Protein structure networks and hydrogen bonds analysis demonstrated that active mutations broke the interaction between activation segments (residues 216–222) and C-helix (residues 105–121) in MEK1, leading to it transform inactive form to active form. Moreover, hydrogen bond analysis and MM-PBSA calculation indicated that activating mutations decrease the binding affinity between MEK1 and inhibitor to reduce the inhibitory effect of inhibitors. In addition, some active mutations cause structural changes in the Pro-rich loop (residues 261–268) of MEK1. These changes may stabilize the interaction between the MEK1 mutants and the ligands by increasing the number of exposed hydrophobic residues in the active site of MEK1. Our results may provide useful theoretical evidences for the mechanism underlying the role of human MEK1 in human cancers. Communicated by Ramaswamy H. Sarma