Mechanistic insight into substrate processing and allosteric inhibition of human p97.
Nat Struct Mol Biol
; 28(7): 614-625, 2021 07.
Article
in English
| MEDLINE | ID: covidwho-1550333
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Signal Transduction
/
Adenosine Triphosphate
/
Protein Folding
/
Valosin Containing Protein
/
Proteostasis
Limits:
Animals
/
Humans
Language:
English
Journal:
Nat Struct Mol Biol
Journal subject:
Molecular Biology
Year:
2021
Document Type:
Article
Affiliation country:
S41594-021-00617-2
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