6HLO

Crystal structure of the Neurokinin 1 receptor in complex with the small molecule antagonist Aprepitant

Summary for 6HLO

• Entry DOI: 10.2210/pdb6hlo/pdb
• Descriptor: Substance-P receptor,GlgA glycogen synthase,Substance-P receptor, 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, CITRIC ACID, ... (6 entities in total)
• Functional Keywords: 7-tm; gpcr; signalling protein, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 65746.17

Authors

Schoppe, J.,Ehrenmann, J.,Klenk, C.,Rucktooa, P.,Schutz, M.,Dore, A.S.,Pluckthun, A. (deposition date: 2018-09-11, release date: 2019-01-16, Last modification date: 2024-01-24)

Primary citation

Schoppe, J.,Ehrenmann, J.,Klenk, C.,Rucktooa, P.,Schutz, M.,Dore, A.S.,Pluckthun, A.
Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists.
Nat Commun, 10:17-17, 2019

PubMed Abstract: Neurokinins (or tachykinins) are peptides that modulate a wide variety of human physiology through the neurokinin G protein-coupled receptor family, implicated in a diverse array of pathological processes. Here we report high-resolution crystal structures of the human NK receptor (NKR) bound to two small-molecule antagonist therapeutics - aprepitant and netupitant and the progenitor antagonist CP-99,994. The structures reveal the detailed interactions between clinically approved antagonists and NKR, which induce a distinct receptor conformation resulting in an interhelical hydrogen-bond network that cross-links the extracellular ends of helices V and VI. Furthermore, the high-resolution details of NKR bound to netupitant establish a structural rationale for the lack of basal activity in NKR. Taken together, these co-structures provide a comprehensive structural basis of NKR antagonism and will facilitate the design of new therapeutics targeting the neurokinin receptor family.

PubMed: 30604743
DOI: 10.1038/s41467-018-07939-8

Experimental method

X-RAY DIFFRACTION (2.4 Å)