9GLA

Crystal structure of a CDK2-based CDK7 mimic with inhibitor SY5609

9GLA の概要

• エントリーDOI: 10.2210/pdb9gla/pdb
• 分子名称: Cyclin-dependent kinase 2, Cyclin-A2, 7-dimethylphosphoryl-3-[2-[[(3~{S})-6,6-dimethylpiperidin-3-yl]amino]-5-(trifluoromethyl)pyrimidin-4-yl]-1~{H}-indole-6-carbonitrile, ... (6 entities in total)
• 機能のキーワード: cyclin-dependent kinase, inhibitor, sy5609, selectivity, structure-assisted inhibitor design, cell cycle
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 64292.23

構造登録者

Skerlova, J.,Krejcirikova, V.,Rezacova, P. (登録日: 2024-08-27, 公開日: 2025-04-02)

主引用文献

Skerlova, J.,Krejcirikova, V.,Perina, M.,Vojackova, V.,Fabry, M.,Krystof, V.,Jorda, R.,Rezacova, P.
CDK2-based CDK7 mimic as a tool for structural analysis: Biochemical validation and crystal structure with SY5609.
Int.J.Biol.Macromol., 294:139117-139117, 2025

PubMed Abstract: Cyclin-dependent kinases (CDKs) regulate cell cycle progression and transcription. CDK7 plays a pivotal role in cell division and proliferation, and the CDK7 gene often exhibits mutations or copy number loss in cancer. Pharmacological targeting of CDK7 has been proposed as a cancer treatment strategy and several inhibitors are currently in clinical trials. As opposed to CDK2, the use of structure-assisted drug design for CDK7 has been limited. We present here CDK2m7, a CDK2-based CDK7 mimic created by mutagenesis of the CDK2 active site pocket. CDK2m7 can be produced in E. coli in a fully active complex with cyclin A2 in high yield and purity. CDK2m7 exhibits a shift in inhibitor selectivity from CDK2 to CDK7 and readily crystallizes. Therefore, it can be used in structure-assisted design of CDK7 inhibitors, as demonstrated by the crystal structure of the complex with inhibitor SY5609. CDK2m7 thus represents a simple and affordable platform for CDK7 rational drug development.

PubMed: 39733900
DOI: 10.1016/j.ijbiomac.2024.139117

実験手法

X-RAY DIFFRACTION (2.18 Å)