Divergent activation patterns of BRS3 revealed by two Chinese herb-derived agonists.
10.1016/j.apsb.2025.06.025
- Author:
Jie LI
1
;
Changyao LI
2
;
Qingtong ZHOU
3
;
Wei HAN
3
;
Mingzhu FANG
4
;
Youwei XU
2
;
Yiting MAI
5
;
Yao ZHANG
1
;
Jiahua CUI
6
;
H Eric XU
2
;
Yan ZHANG
4
;
Wanchao YIN
2
;
Ming-Wei WANG
1
Author Information
1. Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
3. Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
4. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
5. Research Center for Deepsea Bioresources, Sanya 572025, China.
6. School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
- Publication Type:Journal Article
- Keywords:
Bombesin receptor subtype-3;
Chinese herb DSO-5a;
Cryo-EM;
Drug discovery;
Oridonin;
Receptor activation;
Structural pharmacology;
Unliganded
- From:
Acta Pharmaceutica Sinica B
2025;15(10):5231-5243
- CountryChina
- Language:English
-
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-Gq 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.
