Divergent activation patterns of BRS3 revealed by two Chinese herb-derived agonists
文献类型：期刊论文
| 作者 | Li, Jie12; Li, Changyao1,10,11; Zhou, Qingtong9; Han, Wei9; Fang, Mingzhu8; Xu, Youwei11; Mai, Yiting7; Zhang, Yao12; Cui, Jiahua6; Xu, H. Eric1,5,9,11 |
| 刊名 | ACTA PHARMACEUTICA SINICA B
 |
| 出版日期 | 2025-10-01 |
| 卷号 | 15期号:10页码:5231-5243 |
| 关键词 | Bombesin receptor subtype-3 Cryo-EM Structural pharmacology Unliganded Chinese herb DSO-5a Oridonin Receptor activation Drug discovery |
| ISSN号 | 2211-3835 |
| DOI | 10.1016/j.apsb.2025.06.025 |
| 英文摘要 | 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 & ring;A, 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. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| WOS关键词 | PROTEIN ; ORIDONIN ; INFLAMMATION ; SIMULATIONS ; PRESSURE ; FEATURES |
| 资助项目 | Science and Technology of Guangdong Province[2021B0909050003] ; CAS Strategic Priority Research Program[XDB37030103] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Lingang Laboratory[LG-GG-202204-01] ; Lingang Laboratory[2021ZD0203400] ; Hainan Provincial Major Science and Technology Project[ZDKJ2021028] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001594388400010 |
| 出版者 | INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/319708]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Zhang, Yan; Yin, Wanchao; Wang, Ming-Wei |
| 作者单位 | 1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 2.Univ Tokyo, Sch Sci, Dept Chem, Tokyo 1130033, Japan 3.Hainan Med Univ, Engn Res Ctr Trop Med Innovat & Transformat, Sch Pharm, Minist Educ, Haikou 570228, Peoples R China 4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.Shanghai Jiao Tong Univ, Sch Chem & Chem Engn, Shanghai 200240, Peoples R China 7.Res Ctr Deepsea Bioresources, Sanya 572025, Peoples R China 8.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identifica, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China 9.Shanghai Jiao Tong Univ, Natl Res Ctr Translat Med Shanghai, Res Ctr Med Struct Biol, Ruijin Hosp,Sch Med,State Key Lab Med Genom, Shanghai 200025, Peoples R China 10.Lingang Lab, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Li, Jie,Li, Changyao,Zhou, Qingtong,et al. Divergent activation patterns of BRS3 revealed by two Chinese herb-derived agonists[J]. ACTA PHARMACEUTICA SINICA B,2025,15(10):5231-5243. |
| APA | Li, Jie.,Li, Changyao.,Zhou, Qingtong.,Han, Wei.,Fang, Mingzhu.,...&Wang, Ming-Wei.(2025).Divergent activation patterns of BRS3 revealed by two Chinese herb-derived agonists.ACTA PHARMACEUTICA SINICA B,15(10),5231-5243. |
| MLA | Li, Jie,et al."Divergent activation patterns of BRS3 revealed by two Chinese herb-derived agonists".ACTA PHARMACEUTICA SINICA B 15.10(2025):5231-5243. |
入库方式： OAI收割
来源：上海药物研究所
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