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 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.