A three-dimensional model of the human neuropeptide Y(NPY)Y-1 receptor (hY(
1)) was constructed, energy refined and used to simulate molecular receptor
interactions of the peptide ligands NPY, [L31, P34]NPY, peptide YY (PYY) a
nd pancreatic polypeptide (PP), and of the nonpeptide antagonist R-N-2-(dip
henylacetyl)-N-(4-hydroxyphenyl)methyl-argininamide (BIBP3226) and its S-en
antiomer BIBP3435. The best complementarity in charges between the receptor
and the peptides, and the best structural accordance with experimental stu
dies, was obtained with amino acid 1-4 of the peptides interacting with Asp
194, Asp200, Gln201, Phe202 and Trp288 in the receptor. Arg33 and Arg35 of
the peptides formed salt bridges with Asp104 and Asp287, respectively, whil
e Tyr36 interacted in a binding pocket formed by Phe41, Thr42, Tyr100, Asn2
97, His298 and Phe302. Calculated electrostatic potentials around NPY and h
Y(1) molecules indicated that ligand binding is initiated by electrostatic
interactions between a highly positive region in the N- and C-terminal part
s of the peptides, and a negative region in the extracellular receptor doma
ins. Molecular dynamics simulations of NPY and BIBP3226 interactions with t
he receptor indicated rigid body motions of TMH5 and TMH6 upon NPY binding
as mechanisms of receptor activation, and that BIBP3226 may act as an antag
onist by constraining these motions. (C) 1999 Elsevier Science Ltd. All rig
hts reserved.