2. Academic Validation
  3. Targeting Ras-, Rho-, and Rab-family GTPases via a conserved cryptic pocket

Targeting Ras-, Rho-, and Rab-family GTPases via a conserved cryptic pocket

  • Cell. 2024 Sep 6:S0092-8674(24)00908-5. doi: 10.1016/j.cell.2024.08.017.
Johannes Morstein 1,  Victoria Bowcut 1,  Micah Fernando 1,  Yue Yang 2,  Lawrence Zhu 1,  Meredith L Jenkins 3,  John T Evans 3,  Keelan Z Guiley 1,  D Matthew Peacock 1,  Sophie Krahnke 4,  Zhi Lin 5,  Katrine A Taran 6,  Benjamin J Huang 6,  Andrew G Stephen 4,  John E Burke 7,  Felice C Lightstone 2,  Kevan M Shokat 8
Affiliations

Affiliations

  • 1 Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA.
  • 2 Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Lab, Livermore, CA 94550, USA.
  • 3 Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
  • 4 NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
  • 5 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
  • 6 Department of Pediatrics, University of California, San Francisco, CA 94158, USA.
  • 7 Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
  • 8 Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. Electronic address: kevan.shokat@ucsf.edu.
PMID: 39255801 DOI: 10.1016/j.cell.2024.08.017
Abstract

The family of Ras-like GTPases consists of over 150 different members, regulated by an even larger number of guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs) that comprise cellular switch networks that govern cell motility, growth, polarity, protein trafficking, and gene expression. Efforts to develop selective small molecule probes and drugs for these proteins have been hampered by the high affinity of guanosine triphosphate (GTP) and lack of allosteric regulatory sites. This paradigm was recently challenged by the discovery of a cryptic allosteric pocket in the switch II region of K-Ras. Here, we ask whether similar pockets are present in GTPases beyond K-Ras. We systematically surveyed members of the Ras, Rho, and Rab family of GTPases and found that many GTPases exhibit targetable switch II pockets. Notable differences in the composition and conservation of key residues offer potential for the development of optimized inhibitors for many members of this previously undruggable family.

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