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

Jendrik Schöppe, Janosch Ehrenmann, Christoph Klenk, Prakash Rucktooa, Marco Schütz, Andrew S. Doré and Andreas Plückthun ()
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Jendrik Schöppe: University of Zürich
Janosch Ehrenmann: University of Zürich
Christoph Klenk: University of Zürich
Prakash Rucktooa: Sosei Heptares
Marco Schütz: University of Zürich
Andrew S. Doré: Sosei Heptares
Andreas Plückthun: University of Zürich

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07939-8

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