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

  • Acta Pharmacol Sin. 2026 Jun;47(6):1671-1681. doi: 10.1038/s41401-025-01741-1.
Xin Li  #  1  2 ,  Shuai Li  #  1 ,  Hong Shan  1 ,  Qing-Ning Yuan  3 ,  Xin-Heng He  4 ,  Qian He  1  2 ,  Min Zhang  1  2 ,  Yang Li  1  5 ,  Wen Hu  1 ,  Kai Wu  1 ,  H Eric Xu  6  7  8 ,  Li-Hua Zhao  9
Affiliations
  • 1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2. University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3. State Key Laboratory of Medical Genomics, Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 4. Lingang Laboratory, Shanghai, 201100, China.
  • 5. School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 6. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 7. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 8. State Key Laboratory of Medical Genomics, Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
  • 9. State Key Laboratory of Medical Genomics, Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
  • # Contributed equally.
PMID: 41639321 DOI: 10.1038/s41401-025-01741-1
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.

Keywords
NPFF2R; PrRPR; ligand recognition; obesity therapy; prolactin-releasing peptide.
Products