Structural highlights
Function[NK1R_HUMAN] This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: substance P > substance K > neuromedin-K. Publication Abstract from PubMedNeurokinin 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. (19)F-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. Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography.,Chen S, Lu M, Liu D, Yang L, Yi C, Ma L, Zhang H, Liu Q, Frimurer TM, Wang MW, Schwartz TW, Stevens RC, Wu B, Wuthrich K, Zhao Q Nat Commun. 2019 Feb 7;10(1):638. doi: 10.1038/s41467-019-08568-5. PMID:30733446[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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This page was last modified 07:31, 6 March 2019.