Structural highlights
Function[NK1R_HUMAN] This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: substance P > substance K > neuromedin-K. Publication Abstract from PubMedNeurokinins (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. Crystal structures of the human neurokinin 1 receptor in complex with clinically used antagonists.,Schoppe J, Ehrenmann J, Klenk C, Rucktooa P, Schutz M, Dore AS, Pluckthun A Nat Commun. 2019 Jan 3;10(1):17. doi: 10.1038/s41467-018-07939-8. PMID:30604743[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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