Protein Engineering, Vol 10, 109-117, Copyright © 1997 by Oxford University Press
P Du, JA Salon, JA Tamm, C Hou, W Cui, MW Walker, N Adham, DS Dhanoa, I Islam, PJ Vaysse, B Dowling, Y Shifman, N Boyle, H Rueger, T Schmidlin, Y Yamaguchi, TA Branchek, RL Weinshank and C Gluchowski
Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor
(GPCR) superfamily and mediate several physiological responses, such as
blood pressure, food intake, sedation and memory retention. To understand
the interactions between the NPY Y1 receptor subtype and its ligands,
computer modeling was applied to the natural peptide agonist, NPY and a
small molecule antagonist, BIBP3226. An agonist and antagonist binding
domain was elucidated using mutagenesis data for the Y1 receptor as well as
for other GPCR families. The agonist and antagonist ligands which were
investigated appear to share common residues for their interaction within
the transmembrane regions of the Y1 receptor structure, including Gln120,
Asn283 and His306. This is in contrast to findings with tachykinin
receptors where the binding domains of the non-peptide antagonists have
very little in common with the binding domains of the agonist, substance-P.
In addition, a hydrogen bond between the hydroxyl group of Tyr36 of NPY and
the side chain of Gln219, an interaction that is absent in the model
complex between Y1 and the antagonist BIBP3226, is proposed as one of the
potential interactions necessary for receptor activation.
ARTICLES
Modeling the G-protein-coupled neuropeptide Y Y1 receptor agonist and antagonist binding sites
Synaptic Pharmaceutical Corp., Paramus, NJ 07652, USA.
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