5OO0

Cdk2(WT) covalent adduct with D28 at C177

5OO0 の概要

• エントリーDOI: 10.2210/pdb5oo0/pdb
• 分子名称: Cyclin-dependent kinase 2, methyl 4-propanoyl-2,3-dihydroquinoxaline-1-carboxylate (3 entities in total)
• 機能のキーワード: covalent inhibitor, cysteine modification, kinase, allosteric inhibitor, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34636.22

構造登録者

Craven, G.,Morgan, R.M.L.,Mann, D.J. (登録日: 2017-08-04, 公開日: 2018-03-14, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.6 Å)