Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors

• DOI: 10.1038/s42004-024-01267-3
• Publication Date: 2024-08-09T13:04:47Z
• Authors: Purbasha Nandi; Kira DeVore; Feng Wang; Shan Li; Joel D. Walker; Thanh Tung Truong; Matthew G. LaPorte; Peter Wipf; Heidi Schlager; John McCleerey; William Paquette; Rod Carlo A. Colu...; Taiping Gan; Yu-Ping Poh; Petra Fromme; Andrew J. Flint; Mark Wolf; Donna M. Huryn; Tsui-Fen Chou; Po-Lin Chiu
• Keywords: AAA proteins; Triazole; Helix (gastropod)

Human p97 ATPase is crucial in various cellular processes, making it a target for inhibitors to treat cancers, neurological, and infectious diseases. Triazole allosteric have been demonstrated match the efficacy of CB-5083, an ATP-competitive inhibitor, models. However, mechanism not well understood. This study systematically investigates structures new triazole bound both wild-type disease mutant forms measures their effects on function. These bind at interface D1 D2 domains each subunit, shifting surrounding helices altering loop near C-terminal α2 G helix modulate domain-domain communications. A key structural moiety inhibitor affects rotameric conformations interacting side chains, indirectly modulating N-terminal domain conformation R155H mutant. The differential binding provide insights into drug design with enhanced specificity, particularly oncology applications.