7JY5

Structure of human p97 in complex with ATPgammaS and Npl4/Ufd1 (masked around p97)

7JY5 の概要

• エントリーDOI: 10.2210/pdb7jy5/pdb
• EMDBエントリー: 21824 21825 21826 22521
• 分子名称: Transitional endoplasmic reticulum ATPase, MAGNESIUM ION, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER (3 entities in total)
• 機能のキーワード: aaa+ atpase chaperon protein homeostasis, translocase
• 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: 543191.54

構造登録者

Pan, M.,Yu, Y.,Liu, L.,Zhao, M. (登録日: 2020-08-28, 公開日: 2021-01-20, 最終更新日: 2024-03-06)

主引用文献

Pan, M.,Zheng, Q.,Yu, Y.,Ai, H.,Xie, Y.,Zeng, X.,Wang, C.,Liu, L.,Zhao, M.
Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative.
Nat Commun, 12:121-121, 2021

PubMed Abstract: p97, also known as valosin-containing protein (VCP) or Cdc48, plays a central role in cellular protein homeostasis. Human p97 mutations are associated with several neurodegenerative diseases. Targeting p97 and its cofactors is a strategy for cancer drug development. Despite significant structural insights into the fungal homolog Cdc48, little is known about how human p97 interacts with its cofactors. Recently, the anti-alcohol abuse drug disulfiram was found to target cancer through Npl4, a cofactor of p97, but the molecular mechanism remains elusive. Here, using single-particle cryo-electron microscopy (cryo-EM), we uncovered three Npl4 conformational states in complex with human p97 before ATP hydrolysis. The motion of Npl4 results from its zinc finger motifs interacting with the N domain of p97, which is essential for the unfolding activity of p97. In vitro and cell-based assays showed that the disulfiram derivative bis-(diethyldithiocarbamate)-copper (CuET) can bypass the copper transporter system and inhibit the function of p97 in the cytoplasm by releasing cupric ions under oxidative conditions, which disrupt the zinc finger motifs of Npl4, locking the essential conformational switch of the complex.

PubMed: 33402676
DOI: 10.1038/s41467-020-20359-x

実験手法

ELECTRON MICROSCOPY (2.89 Å)