CDK2-based CDK7 mimic as a tool for structural analysis: Biochemical validation and crystal structure with SY5609
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články
PubMed
39733900
DOI
10.1016/j.ijbiomac.2024.139117
PII: S0141-8130(24)09928-8
Knihovny.cz E-zdroje
- Klíčová slova
- Cyclin-dependent kinase, Inhibitor, SY5609, Selectivity, Structure-assisted inhibitor design, X-ray crystallography,
- MeSH
- cyklin-dependentní kinasa 2 * chemie metabolismus genetika MeSH
- cyklin-dependentní kinasy * chemie antagonisté a inhibitory metabolismus genetika MeSH
- inhibitory proteinkinas chemie farmakologie MeSH
- katalytická doména MeSH
- kinasa aktivující cyklin dependentní kinasy MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- molekulární modely MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- CDK2 protein, human MeSH Prohlížeč
- CDK7 protein, human MeSH Prohlížeč
- cyklin-dependentní kinasa 2 * MeSH
- cyklin-dependentní kinasy * MeSH
- inhibitory proteinkinas MeSH
- kinasa aktivující cyklin dependentní kinasy MeSH
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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