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 sig...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 2.9Å,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.展开更多
基金supported by the National Natural Science Foundation of China 82273961(Ming-Wei Wang),82073904(Ming-Wei Wang,China),81872915(Ming-Wei Wang,China),32171189(Wanchao Yin,China),32130022(H.Eric Xu,China)and 82121005(H.Eric Xu,China)the National Key R&D Program of China 2022YFA1302900(Wanchao Yin)and 2022YFC2703105(H.Eric Xu,China)+8 种基金the Youth Innovation Promotion Association of CAS 2021278(Wanchao Yin,China)Zhongshan Municipal Bureau of Science and Technology CXTD2023010(Wanchao Yin,China)High-Level New R&D Institute 2019B090904008(Wanchao Yin,China)High-level Innovative Research Institute from Department of Science and Technology of Guangdong Province 2021B0909050003(Wanchao Yin,China)CAS Strategic Priority Research Program XDB37030103(H.Eric Xu,China)Shanghai Municipal Science and Technology Major Project 2019SHZDZX02(H.Eric Xu,China)the Lingang Laboratory Grant No.LG-GG-202204-01(H.Eric Xu,China)STI2030-Major Project 2021ZD0203400(Qingtong Zhou,China)Hainan Provincial Major Science and Technology Project ZDKJ2021028(Qingtong Zhou,China).
文摘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 2.9Å,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.
