8vq4

CDK2-CyclinE1 in complex with allosteric inhibitor I-125A.

spinqualitylabelsall models 8vq4, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8vq4 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.9Å Ligands: A1AC5, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. An allosteric cyclin E-CDK2 site mapped by paralog hopping with covalent probes.,Zhang Y, Liu Z, Hirschi M, Brodsky O, Johnson E, Won SJ, Nagata A, Bezwada D, Petroski MD, Majmudar JD, Niessen S, VanArsdale T, Gilbert AM, Hayward MM, Stewart AE, Nager AR, Melillo B, Cravatt BF Nat Chem Biol. 2024 Sep 18. doi: 10.1038/s41589-024-01738-7. PMID:39294320 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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