6YL1

Cdk2(F80C) with Covalent Adduct TK37 at F80C

Summary for 6YL1

• Entry DOI: 10.2210/pdb6yl1/pdb
• Descriptor: Cyclin-dependent kinase 2, methyl 4-(cyclopropylmethyl)-1-prop-2-enoyl-2,3-dihydroquinoxaline-6-carboxylate (3 entities in total)
• Functional Keywords: covalent inhibitor, cysteine modification, kinase, allosteric inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34612.20

Authors

Craven, G.,Morgan, R.M.L.,Mann, D.J. (deposition date: 2020-04-06, release date: 2020-07-22, Last modification date: 2024-11-13)

Primary citation

Craven, G.B.,Affron, D.P.,Kosel, T.,Wong, T.L.M.,Jukes, Z.H.,Liu, C.T.,Morgan, R.M.L.,Armstrong, A.,Mann, D.J.
Multiparameter Kinetic Analysis for Covalent Fragment Optimization by Using Quantitative Irreversible Tethering (qIT).
Chembiochem, 21:3417-3422, 2020

PubMed Abstract: Chemical probes that covalently modify cysteine residues in a protein-specific manner are valuable tools for biological investigations. Covalent fragments are increasingly implemented as probe starting points, but the complex relationship between fragment structure and binding kinetics makes covalent fragment optimization uniquely challenging. We describe a new technique in covalent probe discovery that enables data-driven optimization of covalent fragment potency and selectivity. This platform extends beyond the existing repertoire of methods for identifying covalent fragment hits by facilitating rapid multiparameter kinetic analysis of covalent structure-activity relationships through the simultaneous determination of K , k and intrinsic reactivity. By applying this approach to develop novel probes against electrophile-sensitive kinases, we showcase the utility of the platform in hit identification and highlight how multiparameter kinetic analysis enabled a successful fragment-merging strategy.

PubMed: 32659037
DOI: 10.1002/cbic.202000457

Experimental method

X-RAY DIFFRACTION (1.66 Å)