首页|Unfolding rates of 1:1 and 2:1 complex of CX-5461 and c-MYC promoter G-quadruplexes revealed by single-molecule force spectroscopy
Unfolding rates of 1:1 and 2:1 complex of CX-5461 and c-MYC promoter G-quadruplexes revealed by single-molecule force spectroscopy
扫码查看
点击上方二维码区域，可以放大扫码查看
原文链接
NETL
NSTL
万方数据
CX-5461,also known as pidnarulex,is a strong G4 stabilizer and has received FDA fast-track designa-tion for BRCA1-and BRCA2-mutated cancers.However,quantitative measurements of the unfolding rates of CX-5461-G4 complexes which are important for the regulation function of G4s,remain lacking.Here,we employ single-molecule magnetic tweezers to measure the unfolding force distributions of c-MYC G4s in the presence of different concentrations of CX-5461.The unfolding force distributions ex-hibit three discrete levels of unfolding force peaks,corresponding to three binding modes.In combina-tion with a fluorescent quenching assay and molecular docking to previously reported ligand-c-MYC G4 structure,we assigned the～69 pN peak corresponding to the 1∶1(ligand:G4)complex where CX-5461 binds at the G4's 5'-end.The～84 pN peak is attributed to the 2:1 complex where CX-5461 occupies both the 5'and 3'.Furthermore,using the Bell-Arrhenius model to fit the unfolding force distributions,we determined the zero-force unfolding rates of 1∶1,and 2∶1 complexes to be(2.4±0.9)× 10-8 s-1 and(1.4±1.0)× 10-9 s-1 respectively.These findings provide valuable insights for the development of G4-targeted ligands to combat c-MYC-driven cancers.
Hui Peng、Yashuo Zhang、Qun Luo、Xinyu Wang、Huijuan You
展开 >
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation,School of Pharmacy,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,China
College of Physics Science and Technology,Yangzhou University,Yangzhou 225009,China
NETL
NSTL
万方数据
