Direct Modulators of K-Ras-Membrane Interactions

Authors

Johannes Morstein
Rebika Shrestha
Que N Van
César A López
Neha Arora
Marco Tonelli
Hong Liang
De Chen
Yong Zhou
John F Hancock
Andrew G Stephen
Thomas J Turbyville
Kevan M Shokat

Publication Date

9-15-2023

Journal

ACS Chemical Biology

Abstract

Protein-membrane interactions (PMIs) are ubiquitous in cellular signaling. Initial steps of signal transduction cascades often rely on transient and dynamic interactions with the inner plasma membrane leaflet to populate and regulate signaling hotspots. Methods to target and modulate these interactions could yield attractive tool compounds and drug candidates. Here, we demonstrate that the conjugation of a medium-chain lipid tail to the covalent K-Ras(G12C) binder MRTX849 at a solvent-exposed site enables such direct modulation of PMIs. The conjugated lipid tail interacts with the tethered membrane and changes the relative membrane orientation and conformation of K-Ras(G12C), as shown by molecular dynamics (MD) simulation-supported NMR studies. In cells, this PMI modulation restricts the lateral mobility of K-Ras(G12C) and disrupts nanoclusters. The described strategy could be broadly applicable to selectively modulate transient PMIs.

Keywords

ras Proteins, Cell Membrane, Signal Transduction, Molecular Dynamics Simulation, Lipids, Proto-Oncogene Proteins p21(ras)