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TitleStructural insights into hormone recognition and G-protein coupling of the urotensin-II receptor.
Journal, issue, pagesJ Biol Chem, Vol. 301, Issue 11, Page 110794, Year 2025
Publish dateOct 6, 2025
AuthorsTianyu Gao / Chongzhao You / Yinglong Cao / Xiaofang Xu / Qingning Yuan / Shiyi Shen / H Eric Xu / Jia Duan /
PubMed AbstractUrotensin-II (U-II) is a potent vasoconstrictor peptide that interacts with the human urotensin-II receptor (UTR), a class A G protein-coupled receptor (GPCR) that primarily couples with G proteins. ...Urotensin-II (U-II) is a potent vasoconstrictor peptide that interacts with the human urotensin-II receptor (UTR), a class A G protein-coupled receptor (GPCR) that primarily couples with G proteins. In this study, we present the cryo-electron microscopy structure of the miniG-coupled UTR bound to the potent UTR agonist P5U, providing insights into unique ligand recognition and activation mechanisms. Unlike typical linear peptides, the cyclic structure of P5U engages the receptor's transmembrane domains through key side chain interactions involving residues F6, W7, K8, and Y9, which are crucial for receptor activation. Comparative analysis with somatostatin receptors (SSTRs) reveals distinct ligand specificity, driven by variations in side chain composition. Notably, we identify F274 as the toggle switch residue in UTR, in contrast to the classical W seen in other GPCRs. Our findings elucidate the structural basis for UTR's G coupling specificity, highlighting unique Gα interactions. This study advances the understanding of U-II signaling and offers a foundation for developing selective UTR modulators, with potential therapeutic implications for cardiovascular diseases linked to dysregulated U-II activity.
External linksJ Biol Chem / PubMed:41062066 / PubMed Central
MethodsEM (single particle)
Resolution3.23 Å
Structure data

EMDB-61433, PDB-9jfk:
Cryo-EM structure of [Pen5]-urotensin (4-11)-bounded human Urotensin receptor (UTS2R)-Gq complex
Method: EM (single particle) / Resolution: 3.23 Å

Chemicals

ChemComp-CHO:
GLYCOCHENODEOXYCHOLIC ACID / detergent*YM

Source
  • homo sapiens (human)
  • lama glama (llama)
  • synthetic construct (others)
KeywordsSIGNALING PROTEIN / Cryo-EM / GPCR / Urotensin receptor / UTS2R / Gq / agonist / [Pen5]-urotensin (4-11) / complex

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