Entropy drives the ligand recognition in G- protein- coupled receptor subtypes

• 成果类型: Article
• 署名作者: Yang, Xin; Zhou, Pei; Shen, Siyuan; Hu, Qian; Tian, Chenyu; Xia, Anjie; Wang, Yifei; Yang, Zhiqian; Nan, Jinshan; Zhou, Yangli; Chen, Shasha; Tian, Xiaowen; Wu, Chao; Lin, Guifeng; Zhang, Liting; Wang, Kexin; Zheng, Tao; Zou, Jun; Yan, Wei; Shao, Zhenhua; Yang, Shengyong
• 署名单位: Sichuan University; Sichuan University; Sichuan University; Sichuan University; Sichuan University; Sichuan University; Sichuan University; Sichuan University; Tianfu Jincheng Laboratory
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14171
• DOI: 10.1073/pnas.2401091121
• 发表日期: 2024-07-23
• 关键词: cannabinoid receptors; crystal-structures; activation; agonist; cb1; mechanism; DISCOVERY; DYNAMICS

摘要

Achieving ligand subtype selectivitywithin highly homologous subtypes of G- protein- coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism underlying ligand subtype selectivity, which hampers the rational design of subtype- selective ligands. Herein, we disclose an unusual molecular mechanism of entropy- driven ligand recognition in cannabinoid (CB) receptor subtypes, revealed through atomic- level molecular dynamics simulations, cryoelectron microscopy structure, and mutagenesis experiments. This mechanism is attributed to the distinct conformational dynamics of the receptor's orthosteric pocket, leading to variations in ligand binding entropy and consequently, differential binding affinities, which culminate in specific ligand recognition. We experimentally validated this mechanism and leveraged it to design ligands with enhanced or ablated subtype selectivity. One such ligand demonstrated favorable pharmacokinetic properties and significant efficacy in rodent inflammatory analgesic models. More importantly, it is precisely due to the high subtype selectivity obtained based on this mechanism that this ligand does not show addictive properties in animal models. Our findings elucidate the unconventional role of entropy in CB receptor subtype selectivity and suggest a strategy for rational design of ligands to achieve entropy- driven subtype selectivity for many pharmaceutically important GPCRs.