5CYI

CDK2/Cyclin A covalent complex with 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300)

5CYI の概要

• エントリーDOI: 10.2210/pdb5cyi/pdb
• 分子名称: Cyclin-dependent kinase 2, Cyclin-A2, 6-(cyclohexylmethoxy)-N-[4-(ethylsulfonyl)phenyl]-9H-purin-2-amine, ... (4 entities in total)
• 機能のキーワード: cdk2 cyclin a covalent inhibitor vinylsulphone, transferase
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941; Nucleus : P20248
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 129536.08

構造登録者

Anscombe, E.,Meschini, E.,Vidal, R.M.,Martin, M.P.,Staunton, D.,Geitmann, M.,Danielson, U.H.,Stanley, W.A.,Wang, L.Z.,Reuillon, T.,Golding, B.T.,Cano, C.,Newell, D.R.,Noble, M.E.M.,Wedge, S.R.,Endicott, J.A.,Griffin, R.J. (登録日: 2015-07-30, 公開日: 2015-09-16, 最終更新日: 2024-11-13)

主引用文献

Anscombe, E.,Meschini, E.,Mora-Vidal, R.,Martin, M.P.,Staunton, D.,Geitmann, M.,Danielson, U.H.,Stanley, W.A.,Wang, L.Z.,Reuillon, T.,Golding, B.T.,Cano, C.,Newell, D.R.,Noble, M.E.,Wedge, S.R.,Endicott, J.A.,Griffin, R.J.
Identification and Characterization of an Irreversible Inhibitor of CDK2.
Chem.Biol., 22:1159-1164, 2015

PubMed Abstract: Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)-9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.

PubMed: 26320860
DOI: 10.1016/j.chembiol.2015.07.018

実験手法

X-RAY DIFFRACTION (2 Å)