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TitleMolecular basis for cross-activation of NPFF2R by a short PrRP-related peptide.
Journal, issue, pagesActa Pharmacol Sin, Year 2026
Publish dateFeb 4, 2026
AuthorsXin Li / Shuai Li / Hong Shan / Qing-Ning Yuan / Xin-Heng He / Qian He / Min Zhang / Yang Li / Wen Hu / Kai Wu / H Eric Xu / Li-Hua Zhao /
PubMed AbstractProlactin-releasing peptide (PrRP) is an endogenous ligand for the PrRPR, whose activation has been linked to anti-obesity effects. However, PrRP and its analogs also activate the neuropeptide FF ...Prolactin-releasing peptide (PrRP) is an endogenous ligand for the PrRPR, whose activation has been linked to anti-obesity effects. However, PrRP and its analogs also activate the neuropeptide FF receptor 2 (NPFF2R), which is associated with adverse cardiovascular effects. Understanding how PrRP-related peptides differentially engage these two distinct receptors is critical for developing safer, more selective therapeutics. In this study, we present cryo-EM structures of the PrRP analog GUB08248 bound to PrRPR-Gα and NPFF2R-Gα at resolutions of 2.45 Å and 2.85 Å, respectively. These structures reveal a conserved ligand recognition mode across both receptors, while highlighting distinct receptor-specific interactions. The NPFF2R-Gα complex further uncovers key features of receptor activation and G protein coupling. Together, our results offer structural insights that could guide structure-based drug design strategies favoring PrRPR selectivity, thereby advancing the therapeutic potential of the PrRP-PrRPR axis for obesity treatment.
External linksActa Pharmacol Sin / PubMed:41639321
MethodsEM (single particle)
Resolution2.66 - 2.85 Å
Structure data

64674

9v0x

EMDB-64674, PDB-9v0x:
Cryo-EM structure of Gq-coupled PrRPR in complex with GUB08248
Method: EM (single particle) / Resolution: 2.66 Å

64693

9v1h

EMDB-64693, PDB-9v1h:
Cryo-EM structure of Gi-coupled NPFF2R in complex with GUB08248
Method: EM (single particle) / Resolution: 2.85 Å

Chemicals

ChemComp-KUT:
KUT [2-(2-[2-(2-[2-(Octadecandioyl-gamma-Glu)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Prolactin-releasing peptide / PrRPR / complex / NPFF2R

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