Structural insights into ligand recognition, selectivity, and activation of bombesin receptor subtype-3.

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, the lack of known endogenous ligands and high-resolution structure has hindered the understanding of BRS3 signaling and function. We present two cryogenic electron microscopy (cryo-EM) structures of BRS3 in complex with the heterotrimeric G q protein in its active states: one bound to the pan-BnR agonist BA1 and the other bound to the synthetic BRS3-specific agonist MK-5046. These structures reveal the architecture of the orthosteric ligand pocket underpinning molecular recognition and 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. Our findings shed light on BRS3's ligand selectivity and signaling mechanisms, paving the way for exploring its therapeutic potential for diabetes, obesity, and related metabolic disorders. [Display omitted] • Structures of BRS3-G q complexes with ligands BA1 and MK-5046 were determined • Key residues in the ligand-binding pocket for BRS3 activation were identified • Ligand selectivity basis for bombesin receptors was detailed • Binding pocket insights guide rational drug design for BRS3 in diabetes and obesity treatment Li, Xu et al. report cryogenic electron microscopy structures of agonist-bound human bombesin receptor subtype-3 (BRS3) coupled with G protein, revealing insights into ligand recognition, selectivity, and receptor activation. The structures provide a basis for understanding BRS3's role in metabolic regulation and designing modulators targeting this receptor. [ABSTRACT FROM AUTHOR]