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Related Experiment Videos

Ras Binder Induces a Modified Switch-II Pocket in GTP and GDP States.

Daniel R Gentile1, Manoj K Rathinaswamy2, Meredith L Jenkins2

  • 1Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA.

Cell Chemical Biology
|October 17, 2017
PubMed
Summary

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Researchers identified a new ligand, 2C07, that targets the active GTP state of Ras proteins. This discovery offers a new strategy for inhibiting oncogenic Ras mutants, which are predominantly in the GTP state.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Structural Biology

Background:

  • Covalent inhibitors of K-Ras(G12C) typically bind only to the GDP-bound state.
  • Ras proteins cycle between GDP-bound and GTP-bound states, with GTP-bound forms often linked to oncogenic mutations.

Purpose of the Study:

  • To identify novel ligands that bind to the active GTP state of Ras.
  • To characterize the binding site and mechanism of action of a newly identified ligand.
  • To explore therapeutic strategies targeting oncogenic Ras mutants.

Main Methods:

  • Disulfide tethering using a non-natural cysteine (K-Ras(M72C)).
  • Co-crystallography to determine the structure of ligand-bound Ras.
  • Biochemical assays to assess nucleotide binding, exchange, and protein interactions.
Keywords:
GTPaseRascrystallographydrug discoveryhydrogen-deuterium exchange mass spectrometryinhibitorswitch-II pocket

Related Experiment Videos

  • Development and testing of irreversible covalent analogs.

    • Main Results:

    • Identification of a novel switch-II pocket binding ligand (2C07) that engages the GTP state.
    • Co-crystal structures reveal 2C07 binds in a cryptic groove (S-IIG) and disrupts the canonical GTP conformation.
    • 2C07 alters nucleotide preference, inhibits SOS-mediated nucleotide exchange, and inhibits PI3K activation in vitro.
    • Irreversible analogs target both GDP and GTP states and can serve as occupancy probes.

    Conclusions:

    • Targeting the GTP state of Ras with ligands like 2C07 is feasible.
    • This approach offers a potential strategy for inhibiting oncogenic Ras mutants.
    • The developed covalent analogs can target both nucleotide states, broadening therapeutic potential.