8UV2

Human p97/VCP structure with a triazole inhibitor (NSC799462/hexamer)

8UV2 の概要

• エントリーDOI: 10.2210/pdb8uv2/pdb
• EMDBエントリー: 42603
• 分子名称: 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)
• 機能のキーワード: aaa+ atpase, p97, vcp, triazole, allosteric inhibition, motor protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 545315.38

構造登録者

Nandi, P.,DeVore, K.,Chiu, P.-L. (登録日: 2023-11-02, 公開日: 2024-08-21, 最終更新日: 2024-10-02)

主引用文献

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

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: 39122922
DOI: 10.1038/s42004-024-01267-3

実験手法

ELECTRON MICROSCOPY (3.23 Å)