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TitleMechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors.
Journal, issue, pagesCommun Chem, Vol. 7, Issue 1, Page 177, Year 2024
Publish dateAug 9, 2024
AuthorsPurbasha 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 /
PubMed AbstractHuman 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 ...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.
External linksCommun Chem / PubMed:39122922 / PubMed Central
MethodsEM (single particle)
Resolution3.22 - 3.6 Å
Structure data

42603

8uv2

EMDB-42603, PDB-8uv2:
Human p97/VCP structure with a triazole inhibitor (NSC799462/hexamer)
Method: EM (single particle) / Resolution: 3.23 Å

42625

8uvo

EMDB-42625, PDB-8uvo:
Human p97/VCP R155H mutant structure with a triazole inhibitor (NSC804515)
Method: EM (single particle) / Resolution: 3.22 Å

42626

8uvp

EMDB-42626, PDB-8uvp:
Human p97/VCP R155H mutant structure with a triazole inhibitor (NSC819701/up)
Method: EM (single particle) / Resolution: 3.6 Å

42627

8uvq

EMDB-42627, PDB-8uvq:
Human p97/VCP R155H mutant structure with a triazole inhibitor (NSC819701/down)
Method: EM (single particle) / Resolution: 3.42 Å

44748

9boq

EMDB-44748, PDB-9boq:
Human p97/VCP structure with a triazole inhibitor (NSC799462/dodecamer)
Method: EM (single particle) / Resolution: 3.33 Å

Chemicals

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM


ChemComp, No image

ChemComp-XKM:
Unknown entry


ChemComp, No image

ChemComp-XNU:
Unknown entry


ChemComp, No image

ChemComp-XO8:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMOTOR PROTEIN / AAA+ ATPase / p97 / VCP / triazole / allosteric inhibition / MOTOR PROTEIN/INHIBITOR / MOTOR PROTEIN-INHIBITOR complex

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