Crystal structure of NRAS Q61K with a ligand-induced pocket near switch II.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Germany NLM ID: 7906240 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1618-1298 (Electronic) Linking ISSN: 01719335 NLM ISO Abbreviation: Eur J Cell Biol Subsets: MEDLINE
    • Publication Information:
      Publication: Jena, Germany : Elsevier
      Original Publication: Stuttgart : Wissenschaftliche Verlagsgesellschaft, <1979-1997>
    • Subject Terms:
      GTP Phosphohydrolases*/metabolism ; GTP Phosphohydrolases*/genetics ; GTP Phosphohydrolases*/chemistry ; Membrane Proteins*/metabolism ; Membrane Proteins*/genetics ; Membrane Proteins*/chemistry ; Guanosine Triphosphate*/metabolism; Humans ; Crystallography, X-Ray ; Ligands ; Mutation ; Models, Molecular
    • Abstract:
      The RAS isoforms (KRAS, HRAS and NRAS) have distinct cancer type-specific profiles. NRAS mutations are the second most prevalent RAS mutations in skin and hematological malignancies. Although RAS proteins were considered undruggable for decades, isoform and mutation-specific investigations have produced successful RAS inhibitors that are either specific to certain mutants, isoforms (pan-KRAS) or target all RAS proteins (pan-RAS). While extensive structural and biochemical investigations have focused mainly on K- and H-RAS mutations, NRAS mutations have received less attention, and the most prevalent NRAS mutations in human cancers, Q61K and Q61R, are rare in K- and H-RAS. This manuscript presents a crystal structure of the NRAS Q61K mutant in the GTP-bound form. Our structure reveals a previously unseen pocket near switch II induced by the binding of a ligand to the active form of the protein. This observation reveals a binding site that can potentially be exploited for development of inhibitors against mutant NRAS. Furthermore, the well-resolved catalytic site of this GTPase bound to native GTP provides insight into the stalled GTP hydrolysis observed for NRAS-Q61K.
      Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)
    • Contributed Indexing:
      Keywords: Crystal structure; Induced fit; NRAS; Oncogenic mutation; RAS superfamily small GTPases
    • Accession Number:
      EC 3.6.1.- (GTP Phosphohydrolases)
      0 (Membrane Proteins)
      EC 3.6.1.- (NRAS protein, human)
      86-01-1 (Guanosine Triphosphate)
      0 (Ligands)
    • Publication Date:
      Date Created: 20240419 Date Completed: 20240627 Latest Revision: 20240627
    • Publication Date:
      20240628
    • Accession Number:
      10.1016/j.ejcb.2024.151414
    • Accession Number:
      38640594