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

• DOI: 10.1038/s41467-018-07939-8
• Publication Date: 2018-12-28T09:49:23Z
• Authors: Jendrik Schöppe; Janosch Ehrenmann; Christoph Klenk; Prakash Rucktooa; Marco Schütz; Andrew S. Doré; Andreas Plückthun
• Keywords: Pyridines; Science; 610 Medicine & health; 1600 General Chemistry; Molecular Dynamics Simulation; Crystallography, X-Ray; Article; Protein Structure, Secondary; Structure-Activity Relationship; 03 medical and health sciences; Neurokinin-1 Receptor Antagonists; Piperidines; 1300 General Biochemistry, Genetics and Molecular Biology; 10019 Department of Biochemistry; Humans; 0303 health sciences; Binding Sites; Q; Receptors, Neurokinin-1; 3100 General Physics and Astronomy; Recombinant Proteins; 3. Good health; HEK293 Cells; Drug Design; 570 Life sciences; biology; Aprepitant

AbstractNeurokinins (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 NK1receptor (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.