Mechanistic insight into substrate processing and allosteric inhibition of human p97.
Nat Struct Mol Biol
; 28(7): 614-625, 2021 07.
Article
de En
| MEDLINE
| ID: mdl-34262183
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Transduction du signal
/
Adénosine triphosphate
/
Pliage des protéines
/
Protéine contenant la valosine
/
Homéostasie protéique
Limites:
Animals
/
Humans
Langue:
En
Journal:
Nat Struct Mol Biol
Sujet du journal:
BIOLOGIA MOLECULAR
Année:
2021
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique