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Molecular basis for cross-activation of NPFF2R by a short PrRP-related peptide

   
@article{APS11546,
	author = {Xin Li and Shuai Li and Hong Shan and Qing-ning Yuan and Xin-heng He and Qian He and Min Zhang and Yang Li and Wen Hu and Kai Wu and H. Eric Xu and Li-hua Zhao},
	title = {Molecular basis for cross-activation of NPFF2R by a short PrRP-related peptide},
	journal = {Acta Pharmacologica Sinica},
	volume = {47},
	number = {6},
	year = {2026},
	keywords = {},
	abstract = {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-Gαq and NPFF2R-Gαi 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-Gαi 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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/11546}
}