2. Academic Validation
  3. Structural basis of peptide recognition and modulation for neuropeptide FF receptors

Structural basis of peptide recognition and modulation for neuropeptide FF receptors

  • Cell Rep. 2025 Sep 23;44(9):116160. doi: 10.1016/j.celrep.2025.116160.
Xinzhu Li 1,  Heng Zhang 2,  Wen Hu 3,  Kai Wu 3,  Shuai Li 3,  Sanshan Jin 4,  Yuling Yin 4,  Qingning Yuan 5,  H Eric Xu 6,  Benxun Pan 7,  Yi Jiang 8
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; Lingang Laboratory, Shanghai, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS, Shanghai, China.
  • 3 Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, CAS, Shanghai, China.
  • 4 Lingang Laboratory, Shanghai, China.
  • 5 Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, CAS, Shanghai, China; Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, CAS, Shanghai, China; Shanghai Advanced Electron Microscope Center, Shanghai Institute of Materia Medica, CAS, Shanghai, China; Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
  • 7 Lingang Laboratory, Shanghai, China. Electronic address: [email protected].
  • 8 School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; Lingang Laboratory, Shanghai, China. Electronic address: [email protected].
PMID: 40839429 DOI: 10.1016/j.celrep.2025.116160
Abstract

Neuropeptide FF receptors 1 and 2 (NPFFR1 and NPFFR2) are RF-amide peptide receptors that couple to Gi/o proteins and regulate pain, opioid tolerance, and metabolism. Despite their physiological significance, their ligand selectivity and activation mechanisms remain unclear. Using cryoelectron microscopy, we resolved four NPFFR1 and NPFFR2 structures bound to NPFF or NPVF, revealing conserved C-terminal RF-amide interactions within the orthosteric pocket and N-terminal variations driving subtype specificity. Structural and mutagenesis analyses identified ECL2 and the receptor N terminus as key determinants of NPVF-NPFFR1 and NPFF-NPFFR2 selectivity. Additionally, the structures elucidate the activation mechanism and uncover distinct Gi-coupling features between NPFFR subtypes. These findings provide molecular insights into peptide recognition and receptor activation within the RF-amide family, offering a structural framework for designing selective NPFFR modulators to treat pain, addiction, and metabolic disorders with enhanced specificity and reduced off-target effects.

Keywords

CP: Molecular biology; G protein-coupled receptor; RF-amide peptide; neuropeptide FF; neuropeptide FF receptor; neuropeptide VF; selectivity.

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