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

Jendrik Schöppe,Prakash Rucktooa,Andrew S Doré,Christoph Klenk,Andreas Plückthun,Janosch Ehrenmann,Marco Schütz

doi:10.1038/s41467-018-07939-8

Jendrik Schöppe, Prakash Rucktooa + Show 5 more

Open Access

https://doi.org/10.1038/s41467-018-07939-8

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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.

Highlights

Neurokinins 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
The crystal structures of NK1 receptor (NK1R) with CP-99,994 and with aprepitant and netupitant, in use in the clinic today for the treatment of chemotherapyinduced nausea and vomiting (CINV), reveal the structural basis of the successful high-throughput screening and medicinal chemistry campaigns directed towards this receptor spanning several decades
The structures provide a possible molecular rationale for the observed insurmountable antagonism of aprepitant and netupitant. These compounds create an inter-helical hydrogen-bonding network at the extracellular ends of helices V and VI, engaging a “histidine lock” in NK1R across a region known a priori to be important in modulating activity for other class A G protein-coupled receptors (GPCRs)

Summary

Introduction

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. Derived from alternate processing of two genes, the best-characterised mammalian neurokinins are Substance P (SP), NKA and NKB, sharing the conserved C-terminal structural motif FxGLM-NH23 Among other neurokinins, these three peptides act as agonists with different affinities and selectivity for three pharmacologically distinct neurokinin receptors[4]. Disclosure of the first non-peptide NK1R antagonist CP96,34519 (Supplementary Figure 1), discovered by highthroughput screening (HTS), subsequently spurred the development of a number of antagonists with improved pharmacological properties This led to the identification of CP-99,99420, which reduced the chemical structure of CP-96,345 to a molecular scaffold found in many later-stage small-molecule antagonists. We went on to co-crystallise NK1R with two FDA-approved drugs—aprepitant and netupitant

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