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

Nat Commun. 2019 Jan 3;10(1):17. 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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aprepitant / chemistry
  • Aprepitant / pharmacology
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • HEK293 Cells
  • Humans
  • Molecular Dynamics Simulation
  • Neurokinin-1 Receptor Antagonists / chemistry*
  • Neurokinin-1 Receptor Antagonists / pharmacology
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Protein Structure, Secondary
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Receptors, Neurokinin-1 / chemistry*
  • Receptors, Neurokinin-1 / isolation & purification
  • Receptors, Neurokinin-1 / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / isolation & purification
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship


  • Neurokinin-1 Receptor Antagonists
  • Piperidines
  • Pyridines
  • Receptors, Neurokinin-1
  • Recombinant Proteins
  • TACR1 protein, human
  • 3-(2-methoxybenzylamino)-2-phenylpiperidine
  • Aprepitant
  • netupitant