دورية أكاديمية
أعرض في EDS

Proteomic discovery of chemical probes that perturb protein complexes in human cells.

التفاصيل البيبلوغرافية
العنوان: Proteomic discovery of chemical probes that perturb protein complexes in human cells.
المؤلفون: Lazear MR; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Remsberg JR; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA. Electronic address: remsberg@scripps.edu., Jaeger MG; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Rothamel K; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA., Her HL; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA., DeMeester KE; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Njomen E; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Hogg SJ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA., Rahman J; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA., Whitby LR; Vividion Therapeutics, 5820 Nancy Ridge Drive, San Diego, CA 92121, USA., Won SJ; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Schafroth MA; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Ogasawara D; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Yokoyama M; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Lindsey GL; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Li H; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Germain J; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Barbas S; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Vaughan J; Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA, USA., Hanigan TW; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Vartabedian VF; Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA., Reinhardt CJ; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Dix MM; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA., Koo SJ; Molecular and Cellular Pharmacology, Discovery Technologies and Molecular Pharmacology, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium., Heo I; Molecular and Cellular Pharmacology, Discovery Technologies and Molecular Pharmacology, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium., Teijaro JR; Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA., Simon GM; Vividion Therapeutics, 5820 Nancy Ridge Drive, San Diego, CA 92121, USA., Ghosh B; Discovery Chemistry, Janssen Research & Development, Spring House, PA 19477, USA., Abdel-Wahab O; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA., Ahn K; Molecular and Cellular Pharmacology, Discovery Technologies and Molecular Pharmacology, Janssen Research and Development, Spring House, PA 19477, USA., Saghatelian A; Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA, USA., Melillo B; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA; Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA 02142, USA., Schreiber SL; Chemical Biology and Therapeutics Science Program, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA., Yeo GW; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA., Cravatt BF; Department of Chemistry, Scripps Research, La Jolla, CA 92037, USA. Electronic address: cravatt@scripps.edu.
المصدر: Molecular cell [Mol Cell] 2023 May 18; Vol. 83 (10), pp. 1725-1742.e12. Date of Electronic Publication: 2023 Apr 20.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 9802571 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4164 (Electronic) Linking ISSN: 10972765 NLM ISO Abbreviation: Mol Cell Subsets: MEDLINE
أسماء مطبوعة: Publication: Cambridge Ma : Cell Press
Original Publication: Cambridge, Mass. : Cell Press, c1997-
مواضيع طبية MeSH: Proteomics*/methods , Transcription Factors*, Humans ; Cysteine/metabolism ; Ligands
مستخلص: 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.
Competing Interests: 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.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
التعليقات: Comment in: Mol Cell. 2023 May 18;83(10):1544-1546. (PMID: 37207621)
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معلومات مُعتمدة: F32 CA265211 United States CA NCI NIH HHS; R35 CA231991 United States CA NCI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; U24 HG009889 United States HG NHGRI NIH HHS; R01 HG004659 United States HG NHGRI NIH HHS; CGCATF-2021/100012 United Kingdom CRUK_ Cancer Research UK; T32 CA067754 United States CA NCI NIH HHS; R01 CA238249 United States CA NCI NIH HHS; GT15176 United States HHMI Howard Hughes Medical Institute
فهرسة مساهمة: Keywords: activity-based protein profiling; chemical probe; covalent; cysteine; proteasome; protein complexes; proteomics; size-exclusion chromatography; spliceosome
المشرفين على المادة: 0 (Transcription Factors)
K848JZ4886 (Cysteine)
0 (Ligands)
تواريخ الأحداث: Date Created: 20230421 Date Completed: 20230522 Latest Revision: 20240519
رمز التحديث: 20240519
مُعرف محوري في PubMed: PMC10198961
DOI: 10.1016/j.molcel.2023.03.026
PMID: 37084731
قاعدة البيانات: MEDLINE
الوصف
تدمد:1097-4164
DOI:10.1016/j.molcel.2023.03.026