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Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography

文献类型：期刊论文

作者Chen, Shuanghong1,2,3; Lu, Mengjie1,2,3; Liu, Dongsheng4; Yang, Lingyun4; Yi, Cuiying1,2; Ma, Limin1,2; Zhang, Hui1,2,3; Liu, Qing2,5; Frimurer, Thomas M.6; Wang, Ming-Wei2,3,5,7,8
刊名NATURE COMMUNICATIONS
出版日期2019-02-07
卷号10页码:8
ISSN号2041-1723
DOI10.1038/s41467-019-08568-5
通讯作者Wu, Beili(beiliwu@simm.ac.cn) ; Wuthrich, Kurt(wuthrich@scripps.edu) ; Zhao, Qiang(zhaoq@simm.ac.cn)
英文摘要Neurokinin 1 receptor (NK1R) has key regulating functions in the central and peripheral nervous systems, and NK1R antagonists such as aprepitant have been approved for treating chemotherapy-induced nausea and vomiting. However, the lack of data on NK1R structure and biochemistry has limited further drug development targeting this receptor. Here, we combine NMR spectroscopy and X-ray crystallography to provide dynamic and static characterisation of the binding mode of aprepitant in complexes with human NK1R variants. F-19-NMR showed a slow off-rate in the binding site, where aprepitant occupies multiple substates that exchange with frequencies in the millisecond range. The environment of the bound ligand is affected by the amino acid in position 2.50, which plays a key role in ligand binding and receptor signaling in class A GPCRs. Crystal structures now reveal how receptor signaling relates to the conformation of the conserved NP(7.50)xxY motif in transmembrane helix VII.
WOS关键词NK1 RECEPTOR ; NEUROKININ-1 RECEPTOR ; MEMBRANE-PROTEINS ; AMINO-ACID ; MECHANISM ; SEQUENCE ; MUTATION ; TARGET ; POTENT
资助项目National Key R&D Program of China[2018YFA0507000] ; Key Research Program of Frontier Sciences, Chinese Academy of Sciences[QYZDB-SSW-SMC054] ; Key Research Program of Frontier Sciences, Chinese Academy of Sciences[QYZDB-SSW-SMC024] ; National Science Foundation of China[81525024] ; National Science Foundation of China[31825010] ; National Science Foundation of China[31670733]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000458008700017
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/290552]  
专题新药研究国家重点实验室
通讯作者Wu, Beili; Wuthrich, Kurt; Zhao, Qiang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Shanghai Tech Univ, iHuman Inst, 393 Hua Xia Zhong Rd, Shanghai 201210, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China
6.Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Blegdamsvej 3b, DK-2200 Copenhagen, Denmark
7.Fudan Univ, Sch Pharm, 826 Zhangheng Rd, Shanghai 201203, Peoples R China
8.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Hua Xia Zhong Rd, Shanghai 201210, Peoples R China
9.Chinese Acad Sci, CAS Ctr Excellence Biomacromol, Beijing 100101, Peoples R China
10.Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA
推荐引用方式
GB/T 7714		 Chen, Shuanghong,Lu, Mengjie,Liu, Dongsheng,et al. Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography[J]. NATURE COMMUNICATIONS,2019,10:8.
APA Chen, Shuanghong.,Lu, Mengjie.,Liu, Dongsheng.,Yang, Lingyun.,Yi, Cuiying.,...&Zhao, Qiang.(2019).Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography.NATURE COMMUNICATIONS,10,8.
MLA Chen, Shuanghong,et al."Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography".NATURE COMMUNICATIONS 10(2019):8.

入库方式： OAI收割

来源：上海药物研究所

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