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

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 Columbres; Taiping Gan; Yu-Ping Poh; Petra Fromme; Andrew J Flint; Mark Wolf; Donna M Huryn; Tsui-Fen Chou; Po-Lin Chiu

doi:10.1038/s42004-024-01267-3

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

Commun Chem. 2024 Aug 9;7(1):177. doi: 10.1038/s42004-024-01267-3.

Authors

Purbasha Nandi^#^{1

2

3}, Kira DeVore^#^{1

2}, Feng Wang^#⁴, Shan Li⁴, Joel D Walker^{5

6}, Thanh Tung Truong^{5

6

7}, Matthew G LaPorte^{5

6}, Peter Wipf^{5

6}, Heidi Schlager⁸, John McCleerey^{8

9}, William Paquette⁸, Rod Carlo A Columbres^{4

10}, Taiping Gan⁴, Yu-Ping Poh^{2

11}, Petra Fromme^{1

2}, Andrew J Flint¹², Mark Wolf⁸, Donna M Huryn^{5

13

14}, Tsui-Fen Chou^{15

16}, Po-Lin Chiu^{17

18}

Affiliations

¹ School of Molecular Sciences, Arizona State University, Tempe, AZ, USA.
² Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, USA.
³ Biology Department, Brookhaven National Laboratory, Upton, NY, USA.
⁴ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
⁵ University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA, USA.
⁶ Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Faculty of Pharmacy, Phenikaa University, Hanoi, Vietnam.
⁸ Curia Global, Albany, NY, USA.
⁹ Graduate School of Arts and Sciences, Boston University, Boston, MA, USA.
¹⁰ Center for Cancer Research, National Cancer Institute, National Institute of Health, Bethesda, MD, USA.
¹¹ Biodesign Center for Mechanism of Evolution, Arizona State University, Tempe, AZ, USA.
¹² Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
¹³ Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
¹⁴ Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA. [email protected].
¹⁶ Proteome Exploration Laboratory, Beckman Institute, California Institute of Technology, Pasadena, CA, USA. [email protected].
¹⁷ School of Molecular Sciences, Arizona State University, Tempe, AZ, USA. [email protected].
¹⁸ Biodesign Center for Applied Structural Discovery, Arizona State University, Tempe, AZ, USA. [email protected].

^# Contributed equally.

Abstract

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.

Abstract

Grants and funding