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Structural insights into the selective recognition of RF-amide peptides by neuropeptide FF receptor 2

ABSTRACT: Neuropeptide FF Receptor 2 (NPFFR2), a G protein-coupled receptor, plays a role in pain modulation and diet-induced thermogenesis. While NPFFR2 is strongly activated by neuropeptides FF (NPFFs), it shows low activity in response to RF-amide-related peptides (RFRPs), despite the peptides belonging to a shared family. In contrast, NPFFR1, which shares high sequence similarity with NPFFR2, is activated by RFRPs and regulates reproductive hormone balance. The molecular basis for these receptor-specific interactions with their RF-amide peptides remains unclear. Here, we present cryo-electron microscopy structures of NPFFR2 in its active state bound to the agonist RF-amide peptide hNPSF, and in its ligand-free state. Structural analysis reveals that the C-terminal RF-amide moiety engages conserved residues in the transmembrane domain, while the N-terminal segment interacts in a receptor subtype-specific manner. Key selectivity-determining residues in NPFFR2 are also identified. A homology model of NPFFR1 bound to RFRP, supported by mutagenesis studies, further validates this selectivity mechanism. Additionally, structural comparison between the inactive and active states of NPFFR2 demonstrates a TM3-mediated activation mechanism. These findings provide insights into RF-amide peptide recognition by NPFF receptors.

SUBMITTER: Jeesoo Kim

PROVIDER: S-SCDT-10_1038-S44319-025-00428-2 | biostudies-other |

REPOSITORIES: biostudies-other

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