The Plasma Membrane as a Competitive Inhibitor and Positive Allosteric Modulator of KRas4B Signaling.

ABSTRACT: Mutant Ras proteins are important drivers of human cancers, yet no approved drugs act directly on this difficult target. Over the last decade, the idea has emerged that oncogenic signaling can be diminished by molecules that drive Ras into orientations in which effector-binding interfaces are occluded by the cell membrane. To support this approach to drug discovery, we characterize the orientational preferences of membrane-bound K-Ras4B in 1.45-ms aggregate time of atomistic molecular dynamics simulations. Individual simulations probe active or inactive states of Ras on membranes with or without anionic lipids. We find that the membrane orientation of Ras is relatively insensitive to its bound guanine nucleotide and activation state but depends strongly on interactions with anionic phospha

SUBMITTER: Neale C 

PROVIDER: S-EPMC7063485 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature