Activating Mutations Drive Human MEK1 Kinase Using a Gear-Shifting Mechanism

Biochem J. 2023 Oct 23:BCJ20230281. doi: 10.1042/BCJ20230281. Online ahead of print.ABSTRACTThere is an unmet need to classify cancer-promoting kinase mutations in a mechanistically cognizant way. The challenge is to understand mutations stabilize different kinase configurations to alter function, and how this influences pathogenic potential of the kinase and its responses to therapeutic inhibitors. This goal is made more challenging by the complexity of the mutational landscape of diseases, and is further compounded by the conformational plasticity of each variant where multiple conformations co-exist. We focus here on the human MEK1 kinase, a vital component of the RAS/MAPK pathway in which mutations cause cancers and developmental disorders called RASopathies. We sought to explore how these mutations alter the human MEK1 kinase at atomic resolution in by utilizing enhanced sampling simulations and free energy calculations. We computationally mapped the different conformational stabilities of individual mutated systems by delineating the free energy landscapes, and showed how this relates directly to experimentally quantified developmental transformation potentials of the mutations. We conclude that mutations leverage variations in the hydrogen bonding network associated with the conformational plasticity to progressively stabilize the active-like conformational state of the kinase while destabilizing the inactive-like state. The mutations alter residue-level internal molec...
Source: The Biochemical Journal - Category: Biochemistry Authors: Source Type: research