Structural Mass Spectrometry Probes the Inhibitor-Induced Allosteric Activation of CDK12/CDK13-Cyclin K Dissociation.
J Am Chem Soc
; 145(21): 11477-11481, 2023 05 31.
Article
em En
| MEDLINE
| ID: mdl-37207290
ABSTRACT
The rational design and development of effective inhibitors for cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) are largely dependent on the understanding of the dynamic inhibition conformations but are difficult to be achieved by conventional characterization tools. Herein, we integrate the structural mass spectrometry (MS) methods of lysine reactivity profiling (LRP) and native MS (nMS) to systematically interrogate both the dynamic molecular interactions and overall protein assembly of CDK12/CDK13-cyclin K (CycK) complexes under the modulation of small molecule inhibitors. The essential structure insights, including inhibitor binding pocket, binding strength, interfacial molecular details, and dynamic conformation changes, can be derived from the complementary results of LRP and nMS. We find the inhibitor SR-4835 binding can greatly destabilize the CDK12/CDK13-CycK interactions in an unusual allosteric activation way, thereby providing a novel alternative for the kinase activity inhibition. Our results underscore the great potential of LRP combination with nMS for the evaluation and rational design of effective kinase inhibitors at the molecular level.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ciclinas
/
Quinases Ciclina-Dependentes
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China