The Importance of Mg²⁺ -Free State in Nucleotide Exchange of Oncogenic K-Ras Mutants.

ABSTRACT: For efficient targeting of oncogenic K-Ras interaction sites, a mechanistic picture of the Ras-cycle is necessary. Herein, we used NMR relaxation techniques and molecular dynamics simulations to decipher the role of slow dynamics in wild-type and three oncogenic P-loop mutants of K-Ras. Our measurements reveal a dominant two-state conformational exchange on the ms timescale in both GDP- and GTP-bound K-Ras. The identified low-populated higher energy state in GDP-loaded K-Ras has a conformation reminiscent of a nucleotide-bound/Mg²⁺ -free state characterized by shortened β2/β3-strands and a partially released switch-I region preparing K-Ras for the interaction with the incoming nucleotide exchange factor and subsequent reactivation. By providing insight into mutation-specific dif

SUBMITTER: Palfy G 

PROVIDER: S-EPMC9804424 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature