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Nat Commun. 2019 Feb 7;10(1):638. doi: 10.1038/s41467-019-08568-5.

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

Chen S1,2,3, Lu M1,2,3, Liu D4, Yang L4, Yi C1,2, Ma L1,2, Zhang H1,2,3, Liu Q2,5, Frimurer TM6, Wang MW2,3,5,7,8, Schwartz TW6, Stevens RC4,8, Wu B9,10,11,12, Wüthrich K13,14,15, Zhao Q16,17,18,19.

Author information

1
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai, 201203, China.
2
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
3
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
4
iHuman Institute, Shanghai Tech University, 393 Hua Xia Zhong Road, Shanghai, 201210, China.
5
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guo Shou Jing Road, Pudong, Shanghai, 201203, China.
6
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3b, Copenhagen, 2200, Denmark.
7
School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China.
8
School of Life Science and Technology, ShanghaiTech University, 393 Hua Xia Zhong Road, Pudong, Shanghai, 201210, China.
9
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. beiliwu@simm.ac.cn.
10
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. beiliwu@simm.ac.cn.
11
School of Life Science and Technology, ShanghaiTech University, 393 Hua Xia Zhong Road, Pudong, Shanghai, 201210, China. beiliwu@simm.ac.cn.
12
CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, 100101, China. beiliwu@simm.ac.cn.
13
iHuman Institute, Shanghai Tech University, 393 Hua Xia Zhong Road, Shanghai, 201210, China. wuthrich@scripps.edu.
14
School of Life Science and Technology, ShanghaiTech University, 393 Hua Xia Zhong Road, Pudong, Shanghai, 201210, China. wuthrich@scripps.edu.
15
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA. wuthrich@scripps.edu.
16
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai, 201203, China. zhaoq@simm.ac.cn.
17
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. zhaoq@simm.ac.cn.
18
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. zhaoq@simm.ac.cn.
19
CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences, Beijing, 100101, China. zhaoq@simm.ac.cn.

Abstract

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. 19F-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 NP7.50xxY motif in transmembrane helix VII.

PMID:
30733446
PMCID:
PMC6367319
DOI:
10.1038/s41467-019-08568-5
[Indexed for MEDLINE]
Free PMC Article

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