Structural Insights into Ligand Recognition, Selectivity and Activation of the human Bombesin Receptor Subtype-3

Abstract: Bombesin receptor subtype-3 (BRS3) is an important orphan G protein-coupled receptor that regulates energy homeostasis and insulin secretion. As a member of the bombesin receptor (BnR) family, which includes neuromedin B receptor (NMBR) and gastrin-releasing peptide receptor (GRPR), the lack of known endogenous ligands and high-resolution structure has impeded understanding of BRS3 signaling and function. Here, we present cryogenic electron microscopy (cryo-EM) structures of BRS3 in complex with heterotrimeric Gq protein in three states: apo, bound to the pan-BnR agonist, BA1, and bound to the synthetic BRS3-specific agonist MK-5046. These structures reveal the architecture of the orthosteric ligand pocket underpinning molecular recognition. Comparisons with BnR members provide insights into the structural basis for BRS3’s selectivity and low affinity for bombesin peptides. Examination of conserved micro-switches suggests a shared activation mechanism among BnRs. Together our results enable deeper exploration of BRS3’s ligand selectivity, signaling, and therapeutic targeting for diabetes and obesity.