机构：[1]Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[2]New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[3]Department of Ophthalmology and Research Laboratory of Macular Disease, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[4]Engineering Research Center of Medical Information Technology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[5]Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.四川大学华西医院[6]Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China.
Achieving ligand subtype selectivity within 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.
基金：
This work was supported by the National Natural Science
Foundation of China (T2221004, 81930125, and 82130104 to S.Y.; 22277085
to X.Y.; 32371288 to W.Y. and 82103974 to A.X.); National Key R&D Program
of China (2023YFF1204905 to S.Y.); The New Cornerstone Science Foundation;
Ministry of Science and Technology of China (2019YFA0508800 to Z.S.); Major
Project of Guangzhou National Laboratory (GZNL2024A01005 to S.Y.); Sichuan
Science and Technology Program (2024NSFJQ0052 to Z.S. and 2024NSFSC1243
to S.S.); Frontiers Medical Center, Tianfu Jincheng Laboratory Foundation
(TFJC2023010009 to S.Y. and TFJC2023010010 to Z.S.); and 1.3.5 Project for
Disciplines of Excellence, West China Hospital, Sichuan University (ZYXY21001
and ZYGD18001 to S.Y. and -ZYYC23022 to Z.S.);the China Postdoctoral Science
Foundation (2023M732474 and GZB20230480 to S.S.). Cryo-EM data for
CB2-YL025 complex were collected at the West China Cryo-EM Center in Sichuan
University. All Cryo-EM data were processed at SKLB Duyu High Performance
Computing Centre in Sichuan University. This research used resources from the
Duyu High Performance Computing Center, Sichuan University, and Big Data
Platform at West China Hospital of Sichuan University
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2024]版：
无
最新[2023]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.[2]New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.[2]New Cornerstone Science Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.[5]Division of Nephrology and Kidney Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.[6]Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu, Sichuan 610212, China.
推荐引用方式(GB/T 7714)：
Yang Xin,Zhou Pei,Shen Siyuan,et al.Entropy drives the ligand recognition in G-protein-coupled receptor subtypes[J].Proceedings Of The National Academy Of Sciences Of The United States Of America.2024,121(30):e2401091121.doi:10.1073/pnas.2401091121.
APA：
Yang Xin,Zhou Pei,Shen Siyuan,Hu Qian,Tian Chenyu...&Yang Shengyong.(2024).Entropy drives the ligand recognition in G-protein-coupled receptor subtypes.Proceedings Of The National Academy Of Sciences Of The United States Of America,121,(30)
MLA：
Yang Xin,et al."Entropy drives the ligand recognition in G-protein-coupled receptor subtypes".Proceedings Of The National Academy Of Sciences Of The United States Of America 121..30(2024):e2401091121
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