ArticleNature chemical biology2025
An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes.
Article in Nature chemical biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Adaptive mechanisms and emerging cancer therapeutics for CDK2 inhibitors.Nature chemical biology · 2026Review
- Context-dependent synthetic lethality - an emerging precision therapeutic approach.Nature reviews. Cancer · 2026Review
- Complexoform-restricted covalent TRMT112 ligands that allosterically agonize METTL5.Nature chemical biology · 2026Article
- Advances in BRET probes for intracellular target engagement studies.Nature chemical biology · 2026Review
- Emerging Strategies to Inhibit the G1/S Transition for Cancer Therapy.Cancer research · 2026Review
- Cyclin-E/A/CDK1/2 Kinetic Landscapes Drive Cell Cycle Phase-Specific Progression and Guide Cyclin-E Degradation Strategy.Journal of chemical information and modeling · 2026Article
- The Current Toolbox for Covalent Inhibitors: From Hit Identification to Drug Discovery.JACS Au · 2025Review
- Stereoselective Degradation of Diacylglycerol Kinases Potentiate T cell Activation and Tumor Cell Cytotoxicity.bioRxiv : the preprint server for biology · 2025Article
- Tryptoline Stereoprobe Elaboration Identifies Inhibitors of the GRPEL1-HSPA9 Chaperone Complex.bioRxiv : the preprint server for biology · 2025Article
- Targeting CDK2 for cancer therapy.Cell reports · 2025Review
- Multi-tiered chemical proteomic maps of tryptoline acrylamide-protein interactions in cancer cells.Nature chemistry · 2024Article
- Ligand discovery by activity-based protein profiling.Cell chemical biology · 2024Review
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Authors and funding
18 authors.
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Abstract
More than half of the ~20,000 protein-encoding human genes have paralogs. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to subsets of paralogous proteins. Here we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs lacking the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we substituted the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-CCNE1-N112C interaction into in vitro NanoBRET (bioluminescence resonance energy transfer) and in cellulo activity-based protein profiling assays capable of identifying compounds that reversibly inhibit both the N112C mutant and wild-type CCNE1:CDK2 (cyclin-dependent kinase 2) complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings, thus, show how electrophile-cysteine interactions mapped by chemical proteomics can extend the understanding of protein ligandability beyond covalent chemistry.
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