An Activity-Guided Map of Electrophile-Cysteine Interactions in Primary Human T Cells
Open accessAbstract
Electrophilic compounds originating from nature or chemical synthesis have profound effects on immune cells. These compounds are thought to act by cysteine modification to alter the functions of immune-relevant proteins; however, our understanding of electrophile-sensitive cysteines in the human immune proteome remains limited. Here, we present a global map of cysteines in primary human T cells that are susceptible to covalent modification by electrophilic small molecules. More than 3,000 covalently liganded cysteines were found on functionally and structurally diverse proteins, including many that play fundamental roles in immunology. We further show that electrophilic compounds can impair T cell activation by distinct mechanisms involving the direct functional perturbation and/or degradation of proteins. Our findings reveal a rich content of ligandable cysteines in human T cells and point to electrophilic small molecules as a fertile source for chemical probes and ultimately therapeutics that modulate immunological processes and their associated disorders.
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Cysteine ligandability in activated T cells was explored using promiscuous fragment-like scout fragments to map ligandability and functional assays to identify more structurally complex electrophilic compounds that suppress T cell activity.
“Cysteine ligandability has also been explored in activated T cells through the use of promiscuous fragment-like compounds, termed ‘scout fragments’, to map ligandability and functional assays to identify more structurally complex electrophilic compounds that suppress T cell activity182.”
From Advances in covalent drug discovery (2022) · cites this paper as [182]
The approach identified several proteins that could be targeted covalently to impair T cell activity, including BIRC2, BIRC3, the NuRD complex, and kinases ITK and CYTIP.
“this approach was also used to identify several proteins that could be targeted covalently to impair T cell activity, including BIRC2 and BIRC3, the nucleosome remodelling deacetylase (NuRD) complex, and the kinases ITK and CYTIP.”
From Advances in covalent drug discovery (2022) · cites this paper as [182]
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Self-citation
- Authors
- Vinogradova, E. V., Zhang, X., Remillard, D., Lazar, D. C., Suciu, R. M., Wang, Y., Bianco, G., Yamashita, Y., Crowley, V. M., Schafroth, M. A., Yokoyama, M., Konrad, D. B., Lum, K. M., Simon, G. M., Kemper, E. K., Lazear, M. R., Yin, S., Blewett, M. M., Dix, M. M., Nguyen, N., Shokhirev, M. N., Chin, E. N., Lairson, L. L., Melillo, B., Schreiber, S. L., Forli, S., Teijaro, J. R., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- Otsuka (Japan) (JP)
- Vividion Therapeutics (United States) (US)
- Salk Institute for Biological Studies (US)
- Broad Institute (US)
- Corresponding author
- Vinogradova, Ekaterina V.
- Teijaro, John R.
- Cravatt, Benjamin F.
- ORCID
- Vinogradova, Ekaterina V.
- Zhang, Xiaoyu
- Remillard, David
- Lazar, Daniel C.
- Wang, Yujia
- Bianco, Giulia
- Yamashita, Yu
- Crowley, Vincent M.
- Schafroth, Michael A.
- Konrad, David B.
- Lum, Kenneth M.
- Simon, Gabriel M.
- Kemper, Esther K.
- Lazear, Michael R.
- Nguyen, Nhan
- Shokhirev, Maxim N.
- Chin, Emily N.
- Lairson, Luke L.
- Melillo, Bruno
- Schreiber, Stuart L.
- Forli, Stefano
- Teijaro, John R.
- Cravatt, Benjamin F.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 182
- Issue
- 4
- Pages
- 1009-1026.e29
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7775622
- OpenAlex
- W3045530700
- Cited by
- 351
- References
- 93
- Citations by year
- 2026: 51 · 2025: 64 · 2024: 70 · 2023: 78 · 2022: 51 · 2021: 33 · 2020: 4
- FWCI
- 13.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Keywords
- covalent modification, human T cells, T cell activation, protein degradation, chemical probes
- MeSH terms
- Acetamides, Acrylamides, Cells, Cultured, Cysteine, Humans, Ligands, Lymphocyte Activation, Protein-Tyrosine Kinases, Stereoisomerism, T-Lymphocytes, Proteome, Ubiquitin-Protein Ligases, Inhibitor of Apoptosis Proteins, Proteolysis
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.
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