9U4Y

cryo-EM structure of Xenopus laevis GnRHR bound with mammal GnRH

Summary for 9U4Y

• Entry DOI: 10.2210/pdb9u4y/pdb
• Related: 9U4W
• EMDB information: 63858
• Descriptor: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Gonadoliberin-1, ... (6 entities in total)
• Functional Keywords: cryo-em, gnrhr, gonadotropin-releasing hormone receptor, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 162168.05

Authors

Shen, S.,Xu, H.E. (deposition date: 2025-03-20, release date: 2025-06-11, Last modification date: 2025-07-02)

Primary citation

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

Experimental method

ELECTRON MICROSCOPY (2.67 Å)