7LN0

Cryo-EM structure of human p97 in complex with Npl4/Ufd1 and Ub6 (Class 2)

Summary for 7LN0

• Entry DOI: 10.2210/pdb7ln0/pdb
• EMDB information: 23442 23443 23444 23445 23446 23447 23448 23449 23450 23451 23452 23453 23454 23455 23456 23457 23458
• Descriptor: Transitional endoplasmic reticulum ATPase, Hexa-ubiquitin, ADENOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: p97, nms-873, single-particle cryo-em, translocation, allosteric inhibition, translocase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 7
• Total formula weight: 543683.46

Authors

Pan, M.,Yu, Y.,Liu, L.,Zhao, M. (deposition date: 2021-02-06, release date: 2021-09-15, Last modification date: 2024-05-29)

Primary citation

Pan, M.,Yu, Y.,Ai, H.,Zheng, Q.,Xie, Y.,Liu, L.,Zhao, M.
Mechanistic insight into substrate processing and allosteric inhibition of human p97.
Nat.Struct.Mol.Biol., 28:614-625, 2021

PubMed Abstract: p97 processes ubiquitinated substrates and plays a central role in cellular protein homeostasis. Here, we report a series of cryo-EM structures of the substrate-engaged human p97 complex with resolutions ranging from 2.9 to 3.8 Å that captured 'power-stroke'-like motions of both the D1 and D2 ATPase rings of p97. A key feature of these structures is the critical conformational changes of the intersubunit signaling (ISS) motifs, which tighten the binding of nucleotides and neighboring subunits and contribute to the spiral staircase conformation of the D1 and D2 rings. In addition, we determined the cryo-EM structure of human p97 in complex with NMS-873, a potent p97 inhibitor, at a resolution of 2.4 Å. The structures showed that NMS-873 binds at a cryptic groove in the D2 domain and interacts with the ISS motif, preventing its conformational change and thus blocking substrate translocation allosterically.

PubMed: 34262183
DOI: 10.1038/s41594-021-00617-2

Experimental method

ELECTRON MICROSCOPY (2.98 Å)