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

Shuanghong Chen, Mengjie Lu, Dongsheng Liu, Lingyun Yang, Cuiying Yi, Limin Ma, Hui Zhang, Qing Liu, Thomas M. Frimurer, Ming-Wei Wang, Thue W. Schwartz, Raymond C. Stevens, Beili Wu (), Kurt Wüthrich () and Qiang Zhao ()
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Shuanghong Chen: Chinese Academy of Sciences
Mengjie Lu: Chinese Academy of Sciences
Dongsheng Liu: iHuman Institute, Shanghai Tech University
Lingyun Yang: iHuman Institute, Shanghai Tech University
Cuiying Yi: Chinese Academy of Sciences
Limin Ma: Chinese Academy of Sciences
Hui Zhang: Chinese Academy of Sciences
Qing Liu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Thomas M. Frimurer: University of Copenhagen
Ming-Wei Wang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Thue W. Schwartz: University of Copenhagen
Raymond C. Stevens: iHuman Institute, Shanghai Tech University
Beili Wu: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Kurt Wüthrich: iHuman Institute, Shanghai Tech University
Qiang Zhao: Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-8

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08568-5

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