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  2. 上海药物研究所
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Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists

文献类型：期刊论文

作者Sun, Wenjing1; Yang, Fan1; Zhang, Huanhuan1; Yuan, Qingning2; Ling, Shenglong1; Wang, Yuanxia1; Lv, Pei1; Li, Zelin1; Luo, Yifan1; Liu, Dongsheng3
刊名CELL DISCOVERY
出版日期2023-06-30
卷号9期号:1页码:12
DOI10.1038/s41421-023-00564-w
通讯作者Yin, Wanchao(wcyin@simm.ac.cn) ; Shi, Pan(shipan@ustc.edu.cn) ; Xu, H. Eric(eric.xu@simm.ac.cn) ; Tian, Changlin(cltian@ustc.edu.cn)
英文摘要Neurokinin 3 receptor (NK3R) is a tachykinin receptor essential for the hypothalamic-pituitary-gonadal axis. The endogenous peptide agonist neurokinin B (NKB) preferentially activates NK3R, while substance P (SP) binds preferentially to NK1R. In addition, the SP analogue senktide more potently activates NK3R than NKB and SP. However, the mechanisms of preferential binding of peptide and NK3R activation remain elusive. Herein, we determined the cryogenic electron microscopy (cryo-EM) structures of the NK3R-G(q) complex bound to NKB, SP and senktide. The three NK3R-G(q)/peptide complexes utilize a class of noncanonical receptor activation mechanisms. Combining the structural analysis and functional assay illustrated that the consensus C-termini of the three peptide agonists share a conserved binding mode to NK3R, while the divergent N-termini of the peptides confer the preferential binding of the agonist to NK3R. In addition, the specific interactions between the N-terminus of senktide and the N-terminus and extracellular loops (ECL2 and ECL3) of NK3R lead to the improved activation displayed by senktide compared to SP and NKB. These findings pave the way to understand tachykinin receptor subtype selectivity and provide ideas to rationally develop drugs targeting NK3R.
WOS关键词TACHYKININ RECEPTORS ; ARCUATE NUCLEUS ; KISSPEPTIN NEURONS ; NEUROMEDIN-K ; DYNORPHIN-A ; RAT ; NK3 ; EXPRESSION ; SYSTEM ; LOCALIZATION
资助项目National Natural Science Foundation of China[21825703] ; National Natural Science Foundation of China[31971152] ; National Natural Science Foundation of China[22277114] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[32130022] ; National Natural Science Foundation of China[32171189] ; Strategic Priority Research Program of Chinese Academy of Sciences[XDB37000000] ; Strategic Priority Research Program of Chinese Academy of Sciences[XDB37030103] ; Anhui Provincial Natural Science Foundation[2108085J16] ; Collaborative Innovation Program of Hefei Science Center, CAS[2021HSC-CIP011] ; China National Postdoctoral Program for Innovative Talents[BH2340000159] ; Ministry of Science and Technology of China[2018YFA0507002] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; Youth Innovation Promotion Association of CAS[2021278] ; National Science Fund for Excellent Young Scholars[82122067] ; High-level New Ramp;D Institute[2021B0909050003] ; Department of Science and Technology of Guangdong Province[LG202103-03-05] ; Key Tasks of the Lingang Laboratory ; Sanofi Scholarship Program ; [2019B090904008]
WOS研究方向Cell Biology
语种英语
WOS记录号WOS:001022472900002
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/306722]  
专题新药研究国家重点实验室
通讯作者Yin, Wanchao; Shi, Pan; Xu, H. Eric; Tian, Changlin
作者单位1.Univ Sci & Technol China, Affiliated Hosp USTC 1, Dept Endocrinol, Inst Endocrine & Metab Dis,Sch Life Sci,Div Life S, Hefei, Anhui, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
3.ShanghaiTech Univ, iHuman Inst, Shanghai, Peoples R China
4.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Guangdong, Peoples R China
5.Univ Chinese Acad Sci, Beijing, Peoples R China
6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
7.Chinese Acad Sci, Anhui Prov Key Lab High Magnet Resonance Image, High Magnet Field Lab, Hefei, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Sun, Wenjing,Yang, Fan,Zhang, Huanhuan,et al. Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists[J]. CELL DISCOVERY,2023,9(1):12.
APA Sun, Wenjing.,Yang, Fan.,Zhang, Huanhuan.,Yuan, Qingning.,Ling, Shenglong.,...&Tian, Changlin.(2023).Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists.CELL DISCOVERY,9(1),12.
MLA Sun, Wenjing,et al."Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists".CELL DISCOVERY 9.1(2023):12.

入库方式： OAI收割

来源：上海药物研究所

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