Proteomic discovery of chemical probes that perturb protein complexes in human cells.
activity-based protein profiling
chemical probe
covalent
cysteine
proteasome
protein complexes
proteomics
size-exclusion chromatography
spliceosome
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
18 05 2023
18 05 2023
Historique:
received:
10
11
2021
revised:
09
01
2023
accepted:
28
03
2023
pmc-release:
18
05
2024
medline:
22
5
2023
pubmed:
22
4
2023
entrez:
21
04
2023
Statut:
ppublish
Résumé
Most human proteins lack chemical probes, and several large-scale and generalizable small-molecule binding assays have been introduced to address this problem. How compounds discovered in such "binding-first" assays affect protein function, nonetheless, often remains unclear. Here, we describe a "function-first" proteomic strategy that uses size exclusion chromatography (SEC) to assess the global impact of electrophilic compounds on protein complexes in human cells. Integrating the SEC data with cysteine-directed activity-based protein profiling identifies changes in protein-protein interactions that are caused by site-specific liganding events, including the stereoselective engagement of cysteines in PSME1 and SF3B1 that disrupt the PA28 proteasome regulatory complex and stabilize a dynamic state of the spliceosome, respectively. Our findings thus show how multidimensional proteomic analysis of focused libraries of electrophilic compounds can expedite the discovery of chemical probes with site-specific functional effects on protein complexes in human cells.
Identifiants
pubmed: 37084731
pii: S1097-2765(23)00239-3
doi: 10.1016/j.molcel.2023.03.026
pmc: PMC10198961
mid: NIHMS1889442
pii:
doi:
Substances chimiques
Transcription Factors
0
Cysteine
K848JZ4886
Ligands
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1725-1742.e12Subventions
Organisme : NCI NIH HHS
ID : F32 CA265211
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA231991
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NHGRI NIH HHS
ID : U24 HG009889
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG004659
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA238249
Pays : United States
Organisme : Howard Hughes Medical Institute
ID : GT15176
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests G.M.S., V.F.V., and L.R.W. are employees of Vividion Therapeutics, and B.F.C. is a founder and member of the Board of Directors of Vividion Therapeutics. G.W.Y. is a co-founder, member of the Board of Directors, on the SAB, equity holder, and paid consultant for Locanabio and Eclipse BioInnovations. G.W.Y.’s interests have been reviewed and approved by the University of California, San Diego in accordance with its conflict-of-interest policies. A US provisional patent has been filed related to the work disclosed in this manuscript.
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