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From Proteopedia
Cryo-EM structure of neuropeptide FF receptor 2 in the ligand-free state with BRIL fusion, anti-BRIL Fab, and nanobody
Structural highlights
FunctionNPFF2_HUMAN Receptor for NPAF (A-18-F-amide) and NPFF (F-8-F-amide) neuropeptides, also known as morphine-modulating peptides. Can also be activated by a variety of naturally occurring or synthetic FMRF-amide like ligands. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.[1] C562_ECOLX Electron-transport protein of unknown function. Publication Abstract from PubMedNeuropeptide 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 suggests a TM3-mediated activation mechanism. These findings provide insights into RF-amide peptide recognition by NPFF receptors. Structural insights into the selective recognition of RF-amide peptides by neuropeptide FF receptor 2.,Kim J, Hong S, Lee H, Lee HS, Park C, Kim J, Im W, Choi HJ EMBO Rep. 2025 Mar 24. doi: 10.1038/s44319-025-00428-2. PMID:40128413[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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