Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors
Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric p97 inhibitors have been demonstrated to match the efficacy of CB-5083, an ATP-competitive inhibitor, in cellular models. However, the mechanism is not well understood. This study systematically investigates the structures of new triazole inhibitors bound to both wild-type and disease mutant forms of p97 and measures their effects on function. These inhibitors bind at the interface of the D1 and D2 domains of each p97 subunit, shifting surrounding helices and altering the loop structures near the C-terminal α2 G helix to modulate domain-domain communications. A key structural moiety of the inhibitor affects the rotameric conformations of interacting side chains, indirectly modulating the N-terminal domain conformation in p97 R155H mutant. The differential effects of inhibitor binding to wild-type and mutant p97 provide insights into drug design with enhanced specificity, particularly for oncology applications.
Authors
- Andrew Flint (ORCID: https://orcid.org/0000-0002-8340-4726)
- M.E. Wolf (ORCID: https://orcid.org/0000-0003-0690-6789)
- Po‐Lin Chiu (ORCID: https://orcid.org/0000-0001-8608-7650)
- Tsui‐Fen Chou (ORCID: https://orcid.org/0000-0003-2410-2186)
- Peter Wipf (ORCID: https://orcid.org/0000-0001-7693-5863)
- Rod Carlo Columbres (ORCID: https://orcid.org/0000-0002-4134-6054)
- Yu-Ping Poh
- Purbasha Nandi (ORCID: https://orcid.org/0000-0002-8047-2029)
- Taiping Gan
- Donna M. Huryn (ORCID: https://orcid.org/0000-0001-5542-4968)
- William D. Paquette (ORCID: https://orcid.org/0000-0001-8427-7231)
- Trương Thanh Tùng (ORCID: https://orcid.org/0000-0002-5263-203X)
- Kira DeVore (ORCID: https://orcid.org/0000-0003-1325-2947)
- Feng Wang (ORCID: https://orcid.org/0000-0002-2796-5473)
- Petra Fromme
- Joel Walker
- John F. McCleerey (ORCID: https://orcid.org/0000-0001-8901-5935)
- Heidi Schlager
- Matthew G. LaPorte
- Shan Li (ORCID: https://orcid.org/0000-0002-0829-1821)
Institutions
- Boston University (US)
- Leidos (United States) (US)
- California Institute of Technology (US)
- University of Pittsburgh (US)
- Brookhaven National Laboratory (US)
- Phenikaa University (VN)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Arizona State University (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Communications Chemistry
- Published
- 2024-08-09
- DOI
- https://doi.org/10.1038/s42004-024-01267-3
- Citations
- 9
- Primary Topic
- Heat shock proteins research
- Type
- article
- Field-Weighted Citation Impact
- 2.10
Funders
- National Science Foundation
- Nvidia
- Arizona State University
- National Institutes of Health
- Eyring Materials Center, Arizona State University
- National Cancer Institute