Reimagining high-throughput profiling of reactive cysteines for cell-based screening of large electrophile libraries
Open accessAbstract
Current methods used for measuring amino acid side-chain reactivity lack the throughput needed to screen large chemical libraries for interactions across the proteome. Here we redesigned the workflow for activity-based protein profiling of reactive cysteine residues by using a smaller desthiobiotin-based probe, sample multiplexing, reduced protein starting amounts and software to boost data acquisition in real time on the mass spectrometer. Our method, streamlined cysteine activity-based protein profiling (SLC-ABPP), achieved a 42-fold improvement in sample throughput, corresponding to profiling library members at a depth of >8,000 reactive cysteine sites at 18 min per compound. We applied it to identify proteome-wide targets of covalent inhibitors to mutant Kirsten rat sarcoma (KRAS)G12C and Bruton's tyrosine kinase (BTK). In addition, we created a resource of cysteine reactivity to 285 electrophiles in three human cell lines, which includes >20,000 cysteines from >6,000 proteins per line. The goal of proteome-wide profiling of cysteine reactivity across thousand-member libraries under several cellular contexts is now within reach.
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Eight additional cysteine residues on six different proteins display a similar level of competition, indicating apparent labeling by JDQ443, the majority of which are frequently competed by unrelated electrophilic compounds.
“Eight additional cysteine residues on six different proteins display a similar level of competition, indicating apparent labeling by JDQ443, the majority of which are frequently competed by unrelated electrophilic compounds screened in-house and in similar profiling efforts (30).”
SLC-ABPP was used to analyse spleen tissue from C57BL/6 mice treated with ibrutinib.
“SLC-ABPP was used to analyse spleen tissue extracted from C57BL/6 mice treated with ibrutinib183.”
From Advances in covalent drug discovery (2022) · cites this paper as [183]
A TMT-based SLC-ABPP methodology was designed and used to profile an electrophilic fragment library at a depth of more than 8,000 reactive cysteine sites with 18 min total instrument time per compound.
“a tandem mass tag (TMT)-based streamlined cysteine activity-based protein profiling (SLC-ABPP) methodology was designed and used to profile an electrophilic fragment library at an impressive depth of more than 8,000 reactive cysteine sites with a total instrument time of 18 min per compound183.”
From Advances in covalent drug discovery (2022) · cites this paper as [183]
Cys313 on BLK, which like BTK contains a cysteine in the ATP-binding pocket, was also identified as an off-target of ibrutinib.
“Cys313 on B lymphocyte kinase (BLK), which, analogous to BTK, contains a cysteine within the ATP-binding pocket, was also identified as an off-target of ibrutinib183.”
From Advances in covalent drug discovery (2022) · cites this paper as [183]
Among about 9,200 cysteine sites identified, BTK Cys481 was one of the cysteines most liganded by ibrutinib.
“Of ~9,200 cysteine sites identified, BTK Cys481 was one of the cysteines most liganded by ibrutinib.”
From Advances in covalent drug discovery (2022) · cites this paper as [183]
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- Authors
- Kuljanin, M., Mitchell, D. C., Schweppe, D. K., Gikandi, A. S., Nusinow, D. P., Bulloch, N. J., Vinogradova, E. V., Wilson, D. L., Kool, E. T., Mancias, J. D., Cravatt, B. F., & Gygi, S. P.
- Affiliations
- Harvard University (US)
- Scripps Research Institute (US)
- Stanford Cancer Institute (US)
- Corresponding author
- Gygi, Steven P.
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2021-01-04
- Volume
- 39
- Issue
- 5
- Pages
- 630-641
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC8316984
- OpenAlex
- W3120879514
- Cited by
- 305
- References
- 70
- Citations by year
- 2026: 46 · 2025: 68 · 2024: 64 · 2023: 65 · 2022: 42 · 2021: 20
- FWCI
- 19.50
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (GM67945)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Keywords
- activity-based protein profiling, reactive cysteines, sample multiplexing, high-throughput profiling, covalent inhibitors, KRAS G12C, Bruton's tyrosine kinase, cysteine reactivity, cell-based screening
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Amino Acids, Cysteine, Humans, Mass Spectrometry, Proto-Oncogene Proteins p21(ras), Proteome, Proteomics, Antioxidant Response Elements
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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