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TitleMolecular mechanism underlying non-discriminatory recognition of relaxin-3 by RXFP3 and RXFP4.
Journal, issue, pagesCommun Biol, Vol. 8, Issue 1, Page 794, Year 2025
Publish dateMay 23, 2025
AuthorsYan Chen / Qingtong Zhou / Shiyu Yan / Jiahui Yan / Dehua Yang / Jian Chen / Ming-Wei Wang /
PubMed AbstractThe 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 ...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.
External linksCommun Biol / PubMed:40410443 / PubMed Central
MethodsEM (single particle)
Resolution2.91 - 3.1 Å
Structure data

EMDB-62297, PDB-9kfi:
Cryo-EM structure of the human relaxin family peptide receptor 3 in complex with relaxin-3 and G protein
Method: EM (single particle) / Resolution: 2.91 Å

EMDB-62298, PDB-9kfj:
Cryo-EM structure of the compound 4-bound human relaxin family peptide receptor 3 (RXFP3)-Gi complex
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-62299, PDB-9kfk:
Cryo-EM structure of the relaxin-3-bound human relaxin family peptide receptor 4 (RXFP4)-Gi complex
Method: EM (single particle) / Resolution: 2.95 Å

Chemicals

ChemComp-IYF:
1-[2-(4-chlorophenyl)ethyl]-3-[(7-ethyl-5-oxidanyl-1H-indol-3-yl)methylideneamino]guanidine

Source
  • homo sapiens (human)
  • synthetic construct (others)
  • bos taurus (domestic cattle)
  • escherichia coli (E. coli)
KeywordsSTRUCTURAL PROTEN/IMMUNE SYSTEM / human relaxin family peptide receptor 3 / G protein-coupled receptor / ligand recognition / STRUCTURAL PROTEIN / STRUCTURAL PROTEN-IMMUNE SYSTEM complex / STRUCTURAL PROTEIN/IMMUNE SYSTEM / STRUCTURAL PROTEIN-IMMUNE SYSTEM complex / human relaxin family peptide receptor 4

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