6J20

Crystal structure of the human NK1 substance P receptor

Summary for 6J20

• Entry DOI: 10.2210/pdb6j20/pdb
• Descriptor: Substance-P receptor,Endolysin, 5-[[(2~{R},3~{S})-2-[(1~{R})-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)morpholin-4-yl]methyl]-1,2-dihydro-1,2,4-triazol-3-one (2 entities in total)
• Functional Keywords: gpcr, complex, antagonist, signalling protein, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 51019.27

Authors

Chen, S.,Lu, M.,Zhang, H.,Wu, B.,Zhao, Q. (deposition date: 2018-12-30, release date: 2019-03-06, Last modification date: 2024-11-13)

Primary citation

Chen, S.,Lu, M.,Liu, D.,Yang, L.,Yi, C.,Ma, L.,Zhang, H.,Liu, Q.,Frimurer, T.M.,Wang, M.W.,Schwartz, T.W.,Stevens, R.C.,Wu, B.,Wuthrich, K.,Zhao, Q.
Human substance P receptor binding mode of the antagonist drug aprepitant by NMR and crystallography.
Nat Commun, 10:638-638, 2019

PubMed 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. 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 NPxxY motif in transmembrane helix VII.

PubMed: 30733446
DOI: 10.1038/s41467-019-08568-5

Experimental method

X-RAY DIFFRACTION (2.7 Å)