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

被引：35

作者：

Lazear, Michael R. ^{[1
]}

Remsberg, Jarrett R. ^{[1
]}

Jaeger, Martin G. ^{[1
]}

Rothamel, Katherine ^{[2
]}

Her, Hsuan-lin ^{[2
]}

DeMeester, Kristen E. ^{[1
]}

Njomen, Evert ^{[1
]}

Hogg, Simon J. ^{[3
]}

Rahman, Jahan ^{[3
]}

Whitby, Landon R. ^{[4
]}

Won, Sang Joon ^{[1
]}

Schafroth, Michael A. ^{[1
]}

Ogasawara, Daisuke ^{[1
]}

Yokoyama, Minoru ^{[1
]}

Lindsey, Garrett L. ^{[1
]}

Li, Haoxin ^{[1
]}

Germain, Jason ^{[1
]}

Barbas, Sabrina ^{[1
]}

Vaughan, Joan ^{[5
]}

Hanigan, Thomas W. ^{[1
]}

Vartabedian, Vincent F. ^{[5
,6
]}

Reinhardt, Christopher J. ^{[1
]}

Dix, Melissa M. ^{[1
]}

Koo, Seong Joo ^{[7
]}

Heo, Inha ^{[7
]}

Teijaro, John R. ^{[6
]}

Simon, Gabriel M. ^{[4
]}

Ghosh, Brahma ^{[8
]}

Abdel-Wahab, Omar ^{[3
]}

Ahn, Kay ^{[9
]}

Saghatelian, Alan ^{[5
]}

Melillo, Bruno ^{[1
,10
]}

Schreiber, Stuart L. ^{[1
,10
,11
]}

Yeo, Gene W. ^{[2
]}

Cravatt, Benjamin F. ^{[1
]}

机构：

[1] Scripps Res, Dept Chem, La Jolla, CA 92037 USA

[2] Univ Calif La Jolla, Dept Cellular & Mol Med, La Jolla, CA USA

[3] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[4] Vivid Therapeut, 5820 Nancy Ridge Dr, San Diego, CA 92121 USA

[5] Clayton Fdn Labs Peptide Biol, Salk Inst Biol Studies, La Jolla, CA USA

[6] Scripps Res, Dept Immunol & Microbiol, La Jolla, CA 92037 USA

[7] Janssen Res & Dev, Mol & Cellular Pharmacol, Discovery Technol & Mol Pharmacol, Turnhoutseweg 30, B-2340 Beerse, Belgium

[8] Janssen Res & Dev, Discovery Chem, Spring House, PA 19477 USA

[9] Janssen Res & Dev, Mol & Cellular Pharmacol, Discovery Technol & Mol Pharmacol, Spring House, PA 19477 USA

[10] Broad Inst, Chem Biol & Therapeut Sci Program, Cambridge, MA 02142 USA

[11] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA

来源：

MOLECULAR CELL | 2023年 / 83卷 / 10期

关键词：

COVALENT LIGAND DISCOVERY; CONNECTIVITY MAP; SMALL MOLECULES; DRUG DISCOVERY; INHIBITOR; PA28; SF3B; DIVERSITY; BINDING; DESIGN;

D O I：

10.1016/j.molcel.2023.03.026

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Most human proteins lack chemical probes, and several large-scale and generalizable small-molecule bind-ing 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 electro-philic 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 -spe-cific 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, respec-tively. 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.

引用

页码：1725 / +

页数：31

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