5OSM

Cdk2(F80C, C177A) with covalent adduct at C80

Summary for 5OSM

• Entry DOI: 10.2210/pdb5osm/pdb
• Related: 5OO0 5OO1 5OO3 5OSJ
• Descriptor: Cyclin-dependent kinase 2, methyl 1-propanoyl-3,4-dihydro-2~{H}-quinoline-6-carboxylate (3 entities in total)
• Functional Keywords: covalent inhibitor, cysteine modification, kinase, allosteric inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941
• Total number of polymer chains: 1
• Total formula weight: 34559.14

Authors

Craven, G.,Morgan, R.M.L.,Mann, D.J. (deposition date: 2017-08-17, release date: 2018-03-14, Last modification date: 2024-11-20)

Primary citation

Craven, G.B.,Affron, D.P.,Allen, C.E.,Matthies, S.,Greener, J.G.,Morgan, R.M.L.,Tate, E.W.,Armstrong, A.,Mann, D.J.
High-Throughput Kinetic Analysis for Target-Directed Covalent Ligand Discovery.
Angew. Chem. Int. Ed. Engl., 57:5257-5261, 2018

PubMed Abstract: Cysteine-reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine-reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-selective allosteric (type IV) kinase inhibitor whose novel mode-of-action could be exploited therapeutically.

PubMed: 29480525
DOI: 10.1002/anie.201711825

Experimental method

X-RAY DIFFRACTION (1.77 Å)