化学
变构调节
细胞周期蛋白依赖激酶
激酶
合理设计
质谱法
小分子
生物物理学
生物化学
组合化学
立体化学
酶
计算生物学
纳米技术
细胞周期
色谱法
细胞
生物
材料科学
作者
Yu Bai,Zheyi Liu,Yuan‐Qing Li,Heng Zhao,Can Lai,Shan Zhao,Kaixian Chen,Cheng Luo,Xueming Yang,Fangjun Wang
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI