8UV2
Human p97/VCP structure with a triazole inhibitor (NSC799462/hexamer)
Summary for 8UV2
| Entry DOI | 10.2210/pdb8uv2/pdb |
| EMDB information | 42603 |
| Descriptor | Transitional endoplasmic reticulum ATPase, ADENOSINE-5'-DIPHOSPHATE, 3-(4-{[(4P)-5-{[(1R)-cyclohex-2-en-1-yl]sulfanyl}-4-(pyridin-3-yl)-4H-1,2,4-triazol-3-yl]methoxy}-2,6-difluorophenyl)prop-2-yn-1-yl (1-methylpiperidin-4-yl)carbamate (3 entities in total) |
| Functional Keywords | aaa+ atpase, p97, vcp, triazole, allosteric inhibition, motor protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 6 |
| Total formula weight | 545315.38 |
| Authors | Nandi, P.,DeVore, K.,Chiu, P.-L. (deposition date: 2023-11-02, release date: 2024-08-21, Last modification date: 2024-10-02) |
| Primary citation | Nandi, P.,DeVore, K.,Wang, F.,Li, S.,Walker, J.D.,Truong, T.T.,LaPorte, M.G.,Wipf, P.,Schlager, H.,McCleerey, J.,Paquette, W.,Columbres, R.C.A.,Gan, T.,Poh, Y.P.,Fromme, P.,Flint, A.J.,Wolf, M.,Huryn, D.M.,Chou, T.F.,Chiu, P.L. Mechanism of allosteric inhibition of human p97/VCP ATPase and its disease mutant by triazole inhibitors. Commun Chem, 7:177-177, 2024 Cited by PubMed 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. PubMed: 39122922DOI: 10.1038/s42004-024-01267-3 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.23 Å) |
Structure validation
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