9KFI

Cryo-EM structure of the human relaxin family peptide receptor 3 in complex with relaxin-3 and G protein

Summary for 9KFI

• Entry DOI: 10.2210/pdb9kfi/pdb
• EMDB information: 62297
• Descriptor: Soluble cytochrome b562,Relaxin-3 receptor 1,LgBiT, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, Guanine nucleotide-binding protein G(i) subunit alpha-2, ... (7 entities in total)
• Functional Keywords: human relaxin family peptide receptor 3, g protein-coupled receptor, ligand recognition, structural protein, structural proten-immune system complex, structural proten/immune system
• Biological source: Escherichia coli; More
• Total number of polymer chains: 7
• Total formula weight: 199760.31

Authors

Chen, Y.,Zhou, Q.T.,Yan, S.Y.,Yan, J.H.,Yang, D.H.,Chen, J.,Wang, M.W. (deposition date: 2024-11-06, release date: 2025-08-13)

Primary citation

Chen, Y.,Zhou, Q.,Yan, S.,Yan, J.,Yang, D.,Chen, J.,Wang, M.W.
Molecular mechanism underlying non-discriminatory recognition of relaxin-3 by RXFP3 and RXFP4.
Commun Biol, 8:794-794, 2025

PubMed Abstract: The human relaxin family peptide receptors RXFP3 and RXFP4 play important physiological roles through interactions with endogenous hormones, relaxin-3 and insulin-like peptide 5 (INSL5). They are implicated in certain neurological and metabolic disorders. While INSL5 only activates RXFP4, relaxin-3 is recognized by both receptors. Here, we report the cryo-electron microscopy structures of RXFP3-G complexes bound by relaxin-3 or a small-molecule dual agonist (compound 4), and relaxin-3 in complex with RXFP4-G, with global resolutions of 2.91 Å, 2.95 Å, and 3.10 Å, respectively. It is found that relaxin-3 adopts a conserved binding conformation within the transmembrane domain (TMD) bundle of RXFP3 and RXFP4, where the C-terminal tip residues of its B chain, R26 and W27, make extensive contacts with conserved receptor residues, thereby activating RXFP3 and RXFP4. Compound 4 mimics these key interactions by binding to both receptors. In contrast, the C-terminal residues composition and TMD-binding angle of INSL5 in RXFP4 differ significantly from that of relaxin-3, ensuring its selectivity for RXFP4. These findings deepen our understanding about the structural basis of ligand recognition and selectivity in this G protein-coupled receptor subfamily.

PubMed: 40410443
DOI: 10.1038/s42003-025-08220-7

Experimental method

ELECTRON MICROSCOPY (2.91 Å)