9U7R

Substrate-free human 26S proteasome purified by midnolin, 20S proteasome, RPTs and RPN11 part

This is a non-PDB format compatible entry.

Summary for 9U7R

• Entry DOI: 10.2210/pdb9u7r/pdb
• EMDB information: 63943
• Related PRD ID: PRD_000907
• Descriptor: 26S proteasome non-ATPase regulatory subunit 14, Proteasome subunit alpha type-4, Proteasome subunit alpha type-7, ... (26 entities in total)
• Functional Keywords: midnolin, 26s proteasome, complex, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 35
• Total formula weight: 1085313.26

Authors

Zhu, C.,Qin, L.,Liang, L. (deposition date: 2025-03-25, release date: 2026-04-01, Last modification date: 2026-04-08)

Primary citation

Zhu, C.,Qin, L.,Dai, Z.,Zuo, P.,Yang, A.,Zhong, L.,Lin, Z.,Liang, L.
Structural dynamics of the midnolin-proteasome during ubiquitin-independent substrate turnover.
Nat Commun, 17:-, 2026

PubMed Abstract: The 26S proteasome typically degrades proteins marked by ubiquitin chains. However, a distinct, ubiquitin-independent degradation pathway for nuclear proteins exists, mediated by the adaptor protein midnolin, yet its molecular mechanism remains poorly understood. Here, we present nine cryo-electron microscopy structures of the human 26S proteasome in complex with midnolin, which collectively delineate a near-complete catalytic cycle. Our structures reveal that midnolin binds to the proteasome via the RPN1 subunit by its C-terminal helix. Unexpectedly, its ubiquitin-like domain interacts with the RPN11 deubiquitinase in a non-catalytic role. This interaction positions the adjacent Catch domain, which is responsible for substrate binding, directly above the proteasomal entrance, potentially facilitating substrate entry into the proteasome. Furthermore, we observe four consecutive spiral staircase conformations of the AAA+ ATPase hexamer during substrate translocation. These findings provide insights into the mechanisms underlying ubiquitin-independent nuclear protein degradation and may help develop strategies for targeting nuclear proteins via direct proteasomal degradation.

PubMed: 41896529
DOI: 10.1038/s41467-026-71002-0

Experimental method

ELECTRON MICROSCOPY (3.17 Å)