4EOJ

Thr 160 phosphorylated CDK2 H84S, Q85M, K89D - human cyclin A3 complex with ATP

4EOJ の概要

• エントリーDOI: 10.2210/pdb4eoj/pdb
• 関連するPDBエントリー: 4EOI 4EOK 4EOL 4EOM 4EON 4EOO 4EOP 4EOQ 4EOR 4EOS
• 分子名称: Cyclin-dependent kinase 2, Cyclin-A2, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• 機能のキーワード: protein kinase, cell cycle, complex, phosphorylation, transferase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton, centrosome: P24941; Nucleus: P20248
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 129225.44

構造登録者

Echalier, A.,Cot, E.,Camasses, A.,Hodimont, E.,Hoh, F.,Sheinerman, F.,Krasinska, L.,Fisher, D. (登録日: 2012-04-14, 公開日: 2013-02-06, 最終更新日: 2024-11-06)

主引用文献

Echalier, A.,Cot, E.,Camasses, A.,Hodimont, E.,Hoh, F.,Jay, P.,Sheinerman, F.,Krasinska, L.,Fisher, D.
An integrated chemical biology approach provides insight into Cdk2 functional redundancy and inhibitor sensitivity.
Chem.Biol., 19:1028-1040, 2012

PubMed Abstract: Cdk2 promotes DNA replication and is a promising cancer therapeutic target, but its functions appear redundant with Cdk1, an essential Cdk affected by most Cdk2 inhibitors. Here, we present an integrated multidisciplinary approach to address Cdk redundancy. Mathematical modeling of enzymology data predicted conditions allowing selective chemical Cdk2 inhibition. Together with experiments in Xenopus egg extracts, this supports a rate-limiting role for Cdk2 in DNA replication. To confirm this we designed inhibitor-resistant (ir)-Cdk2 mutants using a novel bioinformatics approach. Bypassing inhibition with ir-Cdk2 or with Cdk1 shows that Cdk2 is rate-limiting for replication in this system because Cdk1 is insufficiently active. Additionally, crystal structures and kinetics reveal alternative binding modes of Cdk1-selective and Cdk2-selective inhibitors and mechanisms of Cdk2 inhibitor resistance. Our approach thus provides insight into structure, functions, and biochemistry of a cyclin-dependent kinase.

PubMed: 22921070
DOI: 10.1016/j.chembiol.2012.06.015

実験手法

X-RAY DIFFRACTION (1.65 Å)