Targeting Ras-, Rho-, and Rab-family GTPases via a conserved cryptic pocket
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.
Authors
- John T. Evans (ORCID: https://orcid.org/0000-0003-1007-9675)
- Meredith L. Jenkins (ORCID: https://orcid.org/0000-0002-0685-5048)
- Micah C. Fernando (ORCID: https://orcid.org/0000-0001-9779-0667)
- Felice C. Lightstone (ORCID: https://orcid.org/0000-0003-1465-426X)
- Zhi Lin (ORCID: https://orcid.org/0000-0001-6662-7330)
- Vickie Bowcut (ORCID: https://orcid.org/0000-0002-4934-9225)
- Keelan Z. Guiley (ORCID: https://orcid.org/0000-0002-8149-4262)
- Johannes Morstein (ORCID: https://orcid.org/0000-0002-6940-288X)
- Benjamin J. Huang (ORCID: https://orcid.org/0000-0001-6996-0833)
- Yue Yang (ORCID: https://orcid.org/0000-0001-5670-9551)
- D. Matthew Peacock (ORCID: https://orcid.org/0000-0001-8558-5535)
- Andrew G. Stephen (ORCID: https://orcid.org/0000-0002-8259-621X)
- John E. Burke (ORCID: https://orcid.org/0000-0001-7904-9859)
- Sophie Krahnke
- Lawrence Zhu
- Katrine A. Taran
- Kevan M. Shokat
Institutions
- Lawrence Livermore National Laboratory (US)
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- University of Victoria (CA)
- Frederick National Laboratory for Cancer Research (US)
Publication Details
- Journal
- Cell
- Published
- 2024-09-09
- DOI
- https://doi.org/10.1016/j.cell.2024.08.017
- Citations
- 44
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 10.29
Funders
- U.S. Department of Energy
- Samuel Waxman Cancer Research Foundation
- Frederick National Laboratory for Cancer Research
- Michael Smith Health Research BC
- National Institutes of Health
- Natural Sciences and Engineering Research Council of Canada
- National Cancer Institute
- Lawrence Livermore National Laboratory