9K07

Cryo-EM structure of the DSO-5a-bound human BRS3-Gq complex

This is a non-PDB format compatible entry.

Summary for 9K07

• Entry DOI: 10.2210/pdb9k07/pdb
• EMDB information: 61941
• Descriptor: Bombesin receptor subtype-3,Oplophorus-luciferin 2-monooxygenase catalytic subunit, Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, scFv16, ... (7 entities in total)
• Functional Keywords: dso-5a, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 185640.22

Authors

Li, J.,Li, C.,Zhou, Q.,Han, W.,Fang, M.,Xu, Y.,Mai, Y.,Cui, J.,Xu, H.,Zhang, Y.,Yin, W.,Wang, M. (deposition date: 2024-10-15, release date: 2025-08-27, Last modification date: 2025-11-05)

Primary citation

Li, J.,Li, C.,Zhou, Q.,Han, W.,Fang, M.,Xu, Y.,Mai, Y.,Zhang, Y.,Cui, J.,Xu, H.E.,Zhang, Y.,Yin, W.,Wang, M.W.
Divergent activation patterns of BRS3 revealed by two Chinese herb-derived agonists.
Acta Pharm Sin B, 15:5231-5243, 2025

PubMed Abstract: Bombesin receptor subtype-3 (BRS3) is an orphan G protein-coupled receptor (GPCR) that plays critical roles in energy homeostasis, glucose metabolism, and insulin secretion. Recent structural studies have elucidated BRS3 signaling mechanisms using synthetic ligands, including BA1 and MK-5046. However, the molecular basis of BRS3 activation by bioactive natural compounds and their derivatives, particularly those derived from traditional Chinese medicine, remains unclear. Here, we present high-resolution cryogenic electron microscopy (cryo-EM) structures of the human BRS3-G complex in both unliganded and active states bound by two herb-derived compounds (DSO-5a and oridonin), at resolutions of 2.9, 2.8, and 2.9 Å, respectively. These structures display distinct ligand recognition patterns between DSO-5a and oridonin. Although both compounds bind to the orthosteric pocket, they differentially engage the interaction network of BRS3, as demonstrated by mutagenesis studies assessing calcium mobilization and inositol phosphate 1 (IP1) accumulation. These findings enhance our understanding of BRS3 activation and provide valuable insights into the development of small-molecule BRS3 modulators with therapeutic potential.

PubMed: 41132856
DOI: 10.1016/j.apsb.2025.06.025

Experimental method

ELECTRON MICROSCOPY (2.83 Å)