CDK2-based CDK7 mimic as a tool for structural analysis: Biochemical validation and crystal structure with SY5609.

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Tác giả: Milan Fábry, Radek Jorda, Veronika Krejčiříková, Vladimír Kryštof, Miroslav Peřina, Pavlína Řezáčová, Jana Škerlová, Veronika Vojáčková

Ngôn ngữ: eng

Ký hiệu phân loại: 912.01 Philosophy and theory

Thông tin xuất bản: Netherlands : International journal of biological macromolecules , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 189354

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.
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