Binding modes of noncompetitive AMPA antagonists: a computational approach.
The activity of functional AMPA receptors (AMPARs) is modulated by noncompetitive antagonists. So far, no information about the molecular mechanism of action and the localization of the binding pocket(s) is available. We speculated that the leucine/isoleucine/valine binding protein (LIVBP)-like domain of AMPAR, localized at the extracellular N-terminus of the receptor, might be involved in the binding of noncompetitive antagonists and we tested this hypothesis through a computational approach involving the comparison with NMDA and metabotropic glutamate receptors and the generation of a 3D homology model of the LIVBP-like domain of AMPAR. The results suggest that the interdomain cleft of the LIVBP-like domain of AMPAR may contain the noncompetitive antagonist binding pocket.
De Luca
Laura
L
Dipartimento Farmaco-Chimico, Università di Messina, Viale Annunziata 98168, Messina, Italy.
Macchiarulo
Antonio
A
Costantino
Gabriele
G
Barreca
Maria Letizia
ML
Gitto
Rosaria
R
Chimirri
Alba
A
Pellicciari
Roberto
R
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D019295:Computational Biology / Q000379:methods*; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA