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

• Published in: Nature communications 2019-01, Vol.10 (1), p.17-11, Article 17
• Main Authors: Schöppe, Jendrik, Ehrenmann, Janosch, Klenk, Christoph, Rucktooa, Prakash, Schütz, Marco, Doré, Andrew S., Plückthun, Andreas
• Format: Article
• Language: English
• Subjects: 631/45/612/194; 631/535/1266; 82/80; 82/83; 96/34; Antagonists; Aprepitant - chemistry; Aprepitant - pharmacology; Binding Sites; Coupling (molecular); Crosslinking; Crystal structure; Crystallography, X-Ray; Drug Design; G protein-coupled receptors; HEK293 Cells; Helices; High resolution; Humanities and Social Sciences; Humans; Ligands; Molecular Dynamics Simulation; multidisciplinary; Neurokinin; Neurokinin NK1 receptors; Neurokinin receptors; Neurokinin-1 Receptor Antagonists - chemistry; Neurokinin-1 Receptor Antagonists - pharmacology; Neuropeptides; Peptides; Piperidines - chemistry; Piperidines - pharmacology; Protein Structure, Secondary; Proteins; Pyridines - chemistry; Pyridines - pharmacology; Receptors; Receptors, Neurokinin-1 - chemistry; Receptors, Neurokinin-1 - isolation & purification; Receptors, Neurokinin-1 - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - isolation & purification; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Structure-Activity Relationship
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07939-8

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. Neurokinin receptors are G protein-coupled receptors. Here the authors present three crystal structures of the neurokinin 1 receptor (NK 1 R) in complex with small-molecule antagonists including aprepitant and netupitant and observe that these clinically approved compounds induce a conformational change in the receptor.