Structural basis for specific inhibition of the deubiquitinase UCHL1.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 10 2022
10 10 2022
Historique:
received:
29
04
2022
accepted:
15
09
2022
entrez:
10
10
2022
pubmed:
11
10
2022
medline:
13
10
2022
Statut:
epublish
Résumé
Ubiquitination regulates protein homeostasis and is tightly controlled by deubiquitinases (DUBs). Loss of the DUB UCHL1 leads to neurodegeneration, and its dysregulation promotes cancer metastasis and invasiveness. Small molecule probes for UCHL1 and DUBs in general could help investigate their function, yet specific inhibitors and structural information are rare. Here we report the potent and non-toxic chemogenomic pair of activity-based probes GK13S and GK16S for UCHL1. Biochemical characterization of GK13S demonstrates its stereoselective inhibition of cellular UCHL1. The crystal structure of UCHL1 in complex with GK13S shows the enzyme locked in a hybrid conformation of apo and Ubiquitin-bound states, which underlies its UCHL1-specificity within the UCH DUB family. Phenocopying a reported inactivating mutation of UCHL1 in mice, GK13S, but not GK16S, leads to reduced levels of monoubiquitin in a human glioblastoma cell line. Collectively, we introduce a set of structurally characterized, chemogenomic probes suitable for the cellular investigation of UCHL1.
Identifiants
pubmed: 36216817
doi: 10.1038/s41467-022-33559-4
pii: 10.1038/s41467-022-33559-4
pmc: PMC9549030
doi:
Substances chimiques
UCHL1 protein, human
0
Ubiquitin
0
Ubiquitin Thiolesterase
EC 3.4.19.12
Uchl1 protein, mouse
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5950Informations de copyright
© 2022. The Author(s).
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