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Nat Commun. 2019 Jan 3;10(1):17. doi: 10.1038/s41467-018-07939-8.

Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists.

Author information

1
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland.
2
Sosei Heptares, Steinmetz Building, Granta Park, Great Abington, Cambridge, CB21 6DG, UK.
3
Heptares Therapeutics Zürich AG, Grabenstrasse 11a, 8952, Zürich, Switzerland.
4
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland. plueckthun@bioc.uzh.ch.

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 NK1 receptor (NK1R) 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 NK1R, 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 NK1R bound to netupitant establish a structural rationale for the lack of basal activity in NK1R. Taken together, these co-structures provide a comprehensive structural basis of NK1R antagonism and will facilitate the design of new therapeutics targeting the neurokinin receptor family.

PMID:
30604743
PMCID:
PMC6318301
DOI:
10.1038/s41467-018-07939-8
[Indexed for MEDLINE]
Free PMC Article

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