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

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.