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

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 NK 1 receptor (NK 1 R) 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 NK 1 R, 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 NK 1 R bound to netupitant establish a structural rationale for the lack of basal activity in NK 1 R. Taken together, these co-structures provide a comprehensive structural basis of NK 1 R antagonism and will facilitate the design of new therapeutics targeting the neurokinin receptor family.