8Y52

Cryo-EM structure of the BA1-bound BRS3-Gq complex

Summary for 8Y52

• Entry DOI: 10.2210/pdb8y52/pdb
• EMDB information: 38928
• Descriptor: Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (5 entities in total)
• Functional Keywords: gpcr, bombesin receptor subtype-3 receptor, ba1, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 129138.53

Authors

Li, C.,Xu, Y.,Yin, W.,Xu, H.E. (deposition date: 2024-01-31, release date: 2024-09-11, Last modification date: 2024-10-23)

Primary citation

Li, C.,Xu, Y.,Su, W.,He, X.,Li, J.,Li, X.,Xu, H.E.,Yin, W.
Structural insights into ligand recognition, selectivity, and activation of bombesin receptor subtype-3.
Cell Rep, 43:114511-114511, 2024

PubMed 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, 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 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.

PubMed: 39024101
DOI: 10.1016/j.celrep.2024.114511

Experimental method

ELECTRON MICROSCOPY (2.9 Å)