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

Pálfy, Gyula and K. Menyhárd, Dóra and Ákontz-Kiss, Hanna and Vida, István and Batta, Gyula and Tőke, Orsolya and Perczel, András (2022) The Importance of Mg2 + -Free State in Nucleotide Exchange of Oncogenic K-Ras Mutants. CHEMISTRY-A EUROPEAN JOURNAL, 28. e202201449. ISSN 0947-6539

Preview

Text Manuscript_ChemEurJ_Andras_Perczel_K-Ras_2022.pdf - Accepted Version Download (1MB) | Preview

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 differences in K-Ras structural dynamics, our systematic analysis improves our understanding of prolonged K-Ras signaling and may aid the development of allosteric inhibitors targeting nucleotide exchange in K-Ras.

Actions (login required)

Edit Item