Global profiling of lysine reactivity and ligandability in the human proteome.
- Hacker SM Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92307, USA.
- Backus KM Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92307, USA.
- Lazear MR Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92307, USA.
- Forli S Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California 92307, USA.
- Correia BE Laboratory of Protein Design & Immunoengineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
- Cravatt BF Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92307, USA.
- 2017-11-24
Published in:
- Nature chemistry. - 2017
English
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.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1038/nchem.2826
- PMID 29168484
- Persistent URL
- https://sonar.ch/global/documents/22288
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