EMD-23449
Cryo-EM structure of human p97 in complex with Npl4/Ufd1 and polyubiquitinated Ub-Eos (CHAPSO, Class 1, Close State)
EMD-23449
Single-particle3.09 Å
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Map released: 15/09/2021
Last modified: 29/05/2024
Sample Organism:
Homo sapiens,
Mus musculus
Sample: Human p97 in complex with Npl4/Ufd1 and K48-linked polyubiquitinated Ub-Eos in the presence of ATP
Fitted models: 7ln5 (Avg. Q-score: 0.415)
Deposition Authors: Pan M
,
Yu Y,
Liu L
,
Zhao M
Sample: Human p97 in complex with Npl4/Ufd1 and K48-linked polyubiquitinated Ub-Eos in the presence of ATP
Fitted models: 7ln5 (Avg. Q-score: 0.415)
Deposition Authors: Pan M
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Mechanistic insight into substrate processing and allosteric inhibition of human p97.
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.
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.