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Publication Abstract from PubMed

Prolactin-releasing peptide (PrRP) is an RF-amide neuropeptide that binds and activates its cognate G protein-coupled receptor, prolactin-releasing peptide receptor (PrRPR), also known as GPR10. PrRP and PrRPR are highly conserved across mammals and involved in regulating a range of physiological processes, including stress response, appetite regulation, pain modulation, cardiovascular function, and potentially reproductive functions. Here we present cryo-electron microscopy structures of PrRP-bound PrRPR coupled to G(q) or G(i) heterotrimer, unveiling distinct molecular determinants underlying the specific recognition of the ligand's C-terminal RF-amide motif. We identify a conserved polar pocket that accommodates the C-terminal amide shared by RF-amide peptides. Structural comparison with neuropeptide Y receptors reveals both similarities and differences in engaging the essential RF/RY-amide motifs. Our findings demonstrate the general mechanism governing RF-amide motif recognition by PrRPR and RF-amide peptide receptors, and provide a foundation for elucidating activation mechanisms and developing selective drugs targeting this important peptide-receptor system.

Molecular mechanism of prolactin-releasing peptide recognition and signaling via its G protein-coupled receptor.,Li Y, Yuan Q, He X, Zhang Y, You C, Wu C, Li J, Xu HE, Zhao LH Cell Discov. 2024 Sep 3;10(1):91. doi: 10.1038/s41421-024-00724-6. PMID:39223120^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.