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

• 成果类型: Article
• 署名作者: Shen, Shiyi; He, Xinheng; Liu, Heng; Hu, Wen; Xu, H. Eric; Duan, Jia
• 署名单位: Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; ShanghaiTech University; Chinese Academy of Sciences; Shanghai Institute of Materia Medica, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11462
• DOI: 10.1073/pnas.2500112122
• 发表日期: 2025-06-24
• 关键词: hormone; analogs; antagonist; agonists; environment; validation; expression; management; fertility; receptors

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.