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Cryo- EM structures of GnRHR: Foundations for next- generation therapeutics

文献类型：期刊论文

作者Shen, Shiyi3,4; He, Xinheng3,4; Liu, Heng4; Hu, Wen4; Xu, H. Eric2,3,4; Duan, Jia1,3,4
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2025-06-24
卷号122期号:25页码:10
关键词GnRHR reproductive health therapeutic target Cryo-EM Structure
ISSN号0027-8424
DOI10.1073/pnas.2500112122
英文摘要Gonadotropin-releasing hormone receptor (GnRHR) is critical for reproductive health and a key therapeutic target for endocrine disorders and hormone-responsive cancers. Using high-resolution cryoelectron microscopy, we determined the structures of Sus scrofa and Xenopus laevis GnRHRs bound to mammal GnRH, uncovering conserved and species-specific mechanisms of receptor activation and G protein coupling. The conserved "U"- shaped GnRH conformation mediates high-affinity binding through key interactions with residues such as K3.32, Y6.51, and Y6.52. Species-specific variations in extracellular loops and receptor-ligand contacts fine-tune receptor function, while ligand binding induces structural rearrangements, including N terminus displacement and TM6 rotation, critical for signaling. Structure-activity relationship analysis demonstrates how D-amino acid substitutions in GnRH analogs enhance stability and receptor affinity. Distinct binding modes of agonists and antagonists elucidate mechanisms of ligand-dependent activation and inactivation. These insights lay the groundwork for designing next-generation GnRHR therapeutics with enhanced specificity and efficacy for conditions like endometriosis, prostate cancer, and infertility.
WOS关键词HORMONE ; ANALOGS ; ANTAGONIST ; AGONISTS ; ENVIRONMENT ; VALIDATION ; EXPRESSION ; MANAGEMENT ; FERTILITY ; RECEPTORS
资助项目Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Lingang Laboratory[LG-GG-202204-01] ; National Key R&D Program of China ; [2022YFC2703105]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001521541200001
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/318660]  
专题新药研究国家重点实验室
通讯作者Xu, H. Eric; Duan, Jia
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Shen, Shiyi,He, Xinheng,Liu, Heng,et al. Cryo- EM structures of GnRHR: Foundations for next- generation therapeutics[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2025,122(25):10.
APA Shen, Shiyi,He, Xinheng,Liu, Heng,Hu, Wen,Xu, H. Eric,&Duan, Jia.(2025).Cryo- EM structures of GnRHR: Foundations for next- generation therapeutics.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,122(25),10.
MLA Shen, Shiyi,et al."Cryo- EM structures of GnRHR: Foundations for next- generation therapeutics".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 122.25(2025):10.

入库方式： OAI收割

来源：上海药物研究所

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