National Natural Science Foundation of China (NSFC)
32371255
China
National Natural Science Foundation of China (NSFC)
32071203
China
National Natural Science Foundation of China (NSFC)
32130022
China
National Natural Science Foundation of China (NSFC)
82121005
China
National Natural Science Foundation of China (NSFC)
82404881
China
Citation
Journal: Acta Pharmacol Sin / Year: 2026 Title: Molecular basis for cross-activation of NPFF2R by a short PrRP-related peptide. Authors: Xin 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 / 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 ...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.
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