Molecular Recognition of Itching Neuropeptides by Bombesin Receptors.

Neuromedin B (NMB) and gastrin-releasing peptide (GRP), two bombesin analogs, are endogenous itch-specific neuropeptides that induce histaminergic and nonhistaminergic itch, respectively. Their functions are mediated by two G protein-coupled bombesin receptors, NMBR and GRPR. Here we present cryo-electron microscopy(cryo-EM) structures of G protein coupled NMBR and GRPR bound to NMB and GRP, respectively. The structures reveal that both bombesin receptors contain an extended and deep pocket to adopt NMB and GRP, with the conserved C-terminal motif of GH(F/L)M from both peptides to contact the toggle switch residues for the receptor activation. Together with mutational and functional data, our structures reveal the mechanism of ligand selectivity and specific activation of the bombesin receptors. These findings also pave the way to facilitate rational design of therapies targeting bombesin receptors for the treatment of pruritus.