Global profiling of lysine reactivity and ligandability in the human proteome
Open accessAbstract
Nucleophilic amino acids make important contributions to protein function, including performing key roles in catalysis and serving as sites for post-translational modification. Electrophilic groups that target amino-acid nucleophiles have been used to create covalent ligands and drugs, but have, so far, been mainly limited to cysteine and serine. Here, we report a chemical proteomic platform for the global and quantitative analysis of lysine residues in native biological systems. We have quantified, in total, more than 9,000 lysines in human cell proteomes and have identified several hundred residues with heightened reactivity that are enriched at protein functional sites and can frequently be targeted by electrophilic small molecules. We have also discovered lysine-reactive fragment electrophiles that inhibit enzymes by active site and allosteric mechanisms, as well as disrupt protein-protein interactions in transcriptional regulatory complexes, emphasizing the broad potential and diverse functional consequences of liganding lysine residues throughout the human proteome.
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IsoTOP-ABPP experiments using several lysine-directed probes have proved powerful in profiling lysine reactivity across the proteome.
“IsoTOP-ABPP experiments using several lysine-directed probes have proved powerful in profiling lysine reactivity across the proteome200,201.”
From Advances in covalent drug discovery (2022) · cites this paper as [200]
The authors observed limited overlap of enantioprobe targets with proteins that demonstrated ligandability in previous chemical proteomic studies using cysteine- or lysine-reactive electrophilic fragments.
“We finally observed limited overlap of enantioprobe targets with proteins that demonstrated ligandability in previous chemical proteomic studies using cysteine-26,27 or lysine-reactive28 electrophilic fragments (Fig. 3b)”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [28]
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- Authors
- Hacker, S. M., Backus, K. M., Lazear, M. R., Forli, S., Correia, B. E., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Hacker, Stephan M.
- Backus, Keriann M.
- Cravatt, Benjamin F.
- ORCID
- Venue
- Nature Chemistry
- Published
- 2017-07-31
- Volume
- 9
- Issue
- 12
- Pages
- 1181-1190
- ISSN
- 1755-4330 (ISSN-L)
- 1755-4349
- PMC
- PMC5726523
- OpenAlex
- W2742118221
- Cited by
- 485
- References
- 65
- Citations by year
- 2026: 53 · 2025: 60 · 2024: 59 · 2023: 61 · 2022: 53 · 2021: 67 · 2020: 44 · 2019: 49 · 2018: 32 · 2017: 7
- FWCI
- 15.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (CA087660)
- National Cancer Institute (R01CA132630, R37CA087660, R01CA087660)
- National Institute of General Medical Sciences (F32GM108208, R01GM069832)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- lysine reactivity, chemoproteomics, covalent drug discovery, human proteome, enzyme inhibition, allosteric inhibition, protein-protein interaction, transcriptional regulatory complexes, post-translational modification, nucleophilic amino acids
- MeSH terms
- Humans, Ligands, Lysine, Proteome, Proteomics
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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