9U4W

cryo-EM structure of pig GnRHR bound with mammal GnRH

9U4W の概要

• エントリーDOI: 10.2210/pdb9u4w/pdb
• EMDBエントリー: 63857
• 分子名称: Guanine nucleotide-binding protein G(q) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Gonadoliberin-1, ... (6 entities in total)
• 機能のキーワード: cryo-em, gonadotropin releasing hormone receptor, gnrhr, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 152518.39

構造登録者

Shen, S.,Xu, H.E. (登録日: 2025-03-20, 公開日: 2025-06-11, 最終更新日: 2025-07-02)

主引用文献

Shen, S.,He, X.,Liu, H.,Hu, W.,Xu, H.E.,Duan, J.
Cryo-EM structures of GnRHR: Foundations for next-generation therapeutics.
Proc.Natl.Acad.Sci.USA, 122:e2500112122-e2500112122, 2025

PubMed Abstract: 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 and 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 K, Y, and Y. 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.

PubMed: 40523184
DOI: 10.1073/pnas.2500112122

実験手法

ELECTRON MICROSCOPY (3.18 Å)