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

Nandi, Purbasha; DeVore, Kira; Wang, Feng; Li, Shan; Walker, Joel D.; Truong, Thanh Tung; LaPorte, Matthew G.; Wipf, Peter; Schlager, Heidi; McCleerey, John; Paquette, William; Columbres, Rod Carlo A.; Gan, Taiping; Poh, Yu-Ping; Fromme, Petra; Flint, Andrew J.; Wolf, Mark; Huryn, Donna M.; Chou, Tsui-Fen; Chiu, Po-Lin

doi:10.1038/s42004-024-01267-3

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

Journal Article · Fri Aug 09 00:00:00 EDT 2024 · Communications Chemistry

DOI:https://doi.org/10.1038/s42004-024-01267-3· OSTI ID:2470289

^[1]; DeVore, Kira ^[2]; Wang, Feng ^[3]; Li, Shan ^[3]; Walker, Joel D. ^[4]; ^[5]; LaPorte, Matthew G. ^[4]; ^[4]; Schlager, Heidi ^[6]; ^[7]; ^[6]; Columbres, Rod Carlo A. ^[8]; Gan, Taiping ^[3]; Poh, Yu-Ping ^[2]; Fromme, Petra ^[2]; Flint, Andrew J. ^[9]; Wolf, Mark ^[6]; Huryn, Donna M. ^[10]; ^[3]; ^[2]

Arizona State Univ., Tempe, AZ (United States); Brookhaven National Laboratory (BNL), Upton, NY (United States)
Arizona State Univ., Tempe, AZ (United States)
California Institute of Technology (CalTech), Pasadena, CA (United States)
Univ. of Pittsburgh, PA (United States)
Univ. of Pittsburgh, PA (United States); Phenikaa University (Vietnam)
Curia Global, Albany, NY (United States)
Curia Global, Albany, NY (United States); Boston Univ., MA (United States)
California Institute of Technology (CalTech), Pasadena, CA (United States); National Institutes of Health (NIH), Bethesda, MD (United States)
Leidos Biomedical Research, Inc., Frederick, MD (United States)
Univ. of Pennsylvania, Philadelphia, PA (United States); Univ. of Pittsburgh, PA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0012704

OSTI ID:: 2470289

Journal Information:: Communications Chemistry, Journal Name: Communications Chemistry Journal Issue: 1 Vol. 7; ISSN 2399-3669

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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2.3 A resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition Banerjee, S.; Bartesaghi, A.; Merk, A. Science, Vol. 351, Issue 6275 https://doi.org/10.1126/science.aad7974	journal	January 2016
Targeting acute myeloid leukemia dependency on VCP-mediated DNA repair through a selective second-generation small-molecule inhibitor Roux, Blandine; Vaganay, Camille; Vargas, Jesse D. Science Translational Medicine, Vol. 13, Issue 587 https://doi.org/10.1126/scitranslmed.abg1168	journal	March 2021
Hereditary Inclusion Body Myopathy-Linked p97/VCP Mutations in the NH ₂ Domain and the D1 Ring Modulate p97/VCP ATPase Activity and D2 Ring Conformation Halawani, Dalia; LeBlanc, Andréa C.; Rouiller, Isabelle Molecular and Cellular Biology, Vol. 29, Issue 16 https://doi.org/10.1128/MCB.00252-09	journal	August 2009
Evolutionary Relationships and Structural Mechanisms of aaa+ Proteins Erzberger, Jan P.; Berger, James M. Annual Review of Biophysics and Biomolecular Structure, Vol. 35, Issue 1 https://doi.org/10.1146/annurev.biophys.35.040405.101933	journal	June 2006
Proteotoxic crisis, the ubiquitin-proteasome system, and cancer therapy Deshaies, Raymond J. BMC Biology, Vol. 12, Issue 1 https://doi.org/10.1186/s12915-014-0094-0	journal	November 2014
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Toward an understanding of the Cdc48/p97 ATPase Bodnar, Nicholas; Rapoport, Tom F1000Research, Vol. 6 https://doi.org/10.12688/f1000research.11683.1	journal	January 2017
Mutations in the Human AAA+ Chaperone p97 and Related Diseases Tang, Wai Kwan; Xia, Di Frontiers in Molecular Biosciences, Vol. 3 https://doi.org/10.3389/fmolb.2016.00079	journal	December 2016
The Interplay of Cofactor Interactions and Post-translational Modifications in the Regulation of the AAA+ ATPase p97 Hänzelmann, Petra; Schindelin, Hermann Frontiers in Molecular Biosciences, Vol. 4 https://doi.org/10.3389/fmolb.2017.00021	journal	April 2017
A Mighty “Protein Extractor” of the Cell: Structure and Function of the p97/CDC48 ATPase Ye, Yihong; Tang, Wai Kwan; Zhang, Ting Frontiers in Molecular Biosciences, Vol. 4 https://doi.org/10.3389/fmolb.2017.00039	journal	June 2017
In vitro Development of Chemotherapy and Targeted Therapy Drug-Resistant Cancer Cell Lines: A Practical Guide with Case Studies McDermott, Martina; Eustace, Alex J.; Busschots, Steven Frontiers in Oncology, Vol. 4 https://doi.org/10.3389/fonc.2014.00040	journal	March 2014
Probing Structural Perturbation of Biomolecules by Extracting Cryo-EM Data Heterogeneity DeVore, Kira; Chiu, Po-Lin Biomolecules, Vol. 12, Issue 5 https://doi.org/10.3390/biom12050628	journal	April 2022
Molecular Mechanisms Driving and Regulating the AAA+ ATPase VCP/p97, an Important Therapeutic Target for Treating Cancer, Neurological and Infectious Diseases Valimehr, Sepideh; Sethi, Ashish; Shukla, Manjari Biomolecules, Vol. 13, Issue 5 https://doi.org/10.3390/biom13050737	journal	April 2023
Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes Nandi, Purbasha; Li, Shan; Columbres, Rod Carlo A. International Journal of Molecular Sciences, Vol. 22, Issue 15 https://doi.org/10.3390/ijms22158079	journal	July 2021
The p97 Inhibitor UPCDC-30245 Blocks Endo-Lysosomal Degradation Wang, Feng; Li, Shan; Cheng, Kai-Wen Pharmaceuticals, Vol. 15, Issue 2 https://doi.org/10.3390/ph15020204	journal	February 2022
VCP/p97 is essential for maturation of ubiquitin-containing autophagosomes and this function is impaired by mutations that cause IBMPFD Tresse, Emilie; Salomons, Florian A.; Vesa, Jouni Autophagy, Vol. 6, Issue 2 https://doi.org/10.4161/auto.6.2.11014	journal	February 2010
A Dynamic molecular basis for malfunction in disease mutants of p97/VCP Schuetz, Anne K.; Kay, Lewis E. eLife, Vol. 5 https://doi.org/10.7554/eLife.20143	journal	November 2016
cisTEM, user-friendly software for single-particle image processing Grant, Timothy; Rohou, Alexis; Grigorieff, Nikolaus eLife, Vol. 7 https://doi.org/10.7554/eLife.35383	journal	March 2018

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