Wang Zhangqian, Deng Jieya, Umer Muhammad, Anwar Naureen, Wang Yidang, Dong XingXing, Xu Hua, He Yi, Gao Chao
National R&D Center for Se-rich Agricultural Products Processing, Hubei Engineering Research Center for Deep Processing of Green Se-rich Agricultural Products, School of Modern Industry for Selenium Science and Engineering, Wuhan Polytechnic University Wuhan 430023 China
State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University Wuhan 430062 China.
RSC Adv. 2022 Sep 13;12(40):26011-26015. doi: 10.1039/d2ra03959a. eCollection 2022 Sep 12.
Telomeric G-quadruplexes have been a promising target for developing antitumor drugs with fewer side effects. The intracellular environment is usually in a state of molecular crowding. Studying the interaction mechanism among ligands and telomeric G-quadruplexes under crowded conditions is important for designing drugs that target telomeric G-quadruplexes. In the present study, the telomeric G-quadruplex Tel24 (TTAGGG) was found to fold into a conformational ensemble of parallel and (3 + 1) hybrid-2 conformations in solution with molecular crowding conditions created by PEG200. G-quadruplex-ligand 3,11-difluoro-6,8,13-trimethyl-8-quino[4,3,2-] acridinium methosulfate (RHPS4) preferentially stabilized the (3 + 1) hybrid-2 conformation and shifted the conformational ensemble equilibrium of Tel24 towards the hybrid conformation. We also found that the (3 + 1) hybrid-2 conformation of Tel24 was more likely to form as compared to the parallel conformation in the conformational ensemble of Tel24. Overall, this study provides new insights into the conformation of telomere G-quadruplexes and their interactions with ligands in a physiological environment.
端粒G-四链体一直是开发副作用较少的抗肿瘤药物的一个有前景的靶点。细胞内环境通常处于分子拥挤状态。研究在拥挤条件下配体与端粒G-四链体之间的相互作用机制对于设计靶向端粒G-四链体的药物很重要。在本研究中，发现端粒G-四链体Tel24（TTAGGG）在由PEG200产生分子拥挤条件的溶液中折叠成平行和（3 + 1）杂合-2构象的构象集合。G-四链体配体3,11-二氟-6,8,13-三甲基-8-喹诺[4,3,2-]吖啶鎓甲基硫酸盐（RHPS4）优先稳定（3 + 1）杂合-2构象，并使Tel24的构象集合平衡向杂合构象移动。我们还发现，与Tel24构象集合中的平行构象相比，Tel24的（3 + 1）杂合-2构象更有可能形成。总体而言，本研究为端粒G-四链体在生理环境中的构象及其与配体的相互作用提供了新的见解。
