The extracellular domain of the neurokinin-1 receptor is required for high affinity binding of peptides

Comparison of tachykinin NK1 and NK2 receptors in the circular muscle of the guinea‐pig ileum and proximal colon

“…Our previous observations (Meini et al, 1994) (Petitet et al, 1992). Since the recognition epitopes for certain NK, receptor antagonists by the NK, receptor protein appear to be distinct from the agonist binding site(s) (Gether et al, 1993) (Fong et al, 1992a (Fong et at., 1992a see also Hermans et at., 1993), in sharp contrast with the high potency of this hexapeptide in various bioassays (e.g. Laufer et al, 1988;Hall & Morton, 1991; and present data).…”

Mapping Substance P Binding Sites on the Neurokinin-1 Receptor Using Genetic Incorporation of a Photoreactive Amino Acid

“…Genetic and biochemical evidence indicate that the N terminus of NK1 acts as an important determinant for ligand binding (8,9). Specifically, mutational analysis has verified that residues 23-25 are strongly required for proper binding of SP.…”

“…Ligand-based cross-linking has previously identified a similar fragment of the N terminus to be in proximity to the ligand (14, 16). We did not probe residue numbers 23-25 as they previously have been shown by mutational analysis to be essential for SP binding (8,9). The high resolution x-ray structure of the closely related neurotensin receptor has shown that the corresponding peptide ligand interacts with a large number of residues in the receptor, including Leu-55 and Asp-56 in the Nt segment (25).…”

“…Numerous studies have aimed at identifying regions in the NK1 receptor involved in the binding of its ligands (2,4,8,9,17,18,(35)(36)(37)(38). This receptor is of particular interest because it can bind three different endogenous peptides as well as a number of synthetic ligands, one of which is an antiemetic drug on the market (3,5,39,40).…”

“…We re-examined ligand interaction to this portion of the receptor by generating receptor variants, in which a single residue was substituted with BzF for each of the positions 11-21. It is worth noting that substitution of the two potential N-glycosylation sites Asn-14 or Asn-18 of NK1 does not seem to interfere with binding of SP (8).…”