Structural insights into prolactin-releasing peptide receptor signaling and G-protein coupling selectivity

Prolactin-releasing peptide receptor (PrRPR), a notable member of the class A peptide-GPCR (G-protein- coupled receptor) family, regulates diverse physiology functions upon activation by PrRP. Herein, we reveal that PrRPR could engage with not only the Gq/11 pathway but also the Gi/o pathway. We further resolve the structures of the PrRPR-Gq and PrRPR-Gi complexes using cryoelectron microscopy (cryo-EM), with PrRP31 as the endogenous ligand. These high-resolution structures enhance our understanding of PrRPR-ligand interactions, aiding the development of targeted drugs aiming at this crucial peptide-receptor system. Comparing these structures with counterparts of other RF-amide peptide receptors accentuates the crucial function of the RF-amide motif in activating receptors and sheds light on the universal mechanism for RF-amide motif detection by RF-amide receptors. Furthermore, structural and functional analysis indicates that conformational alterations in the intracellular loops (ICLs), along with the "wavy hook"of Ga, may explain the selective coupling of G proteins in PrRPR signaling.