Structural basis for understanding structure-activity relationships for the glutamate binding site of the NMDA receptor.
We present new homology-based models of the glutamate binding site (in closed and open forms) of the NMDA receptor NR2B subunit derived from X-ray structures of the water soluble AMPA sensitive glutamate receptor. The models were used for revealing binding modes of agonists and competitive antagonists, as well as for rationalizing known experimental facts concerning structure-activity relationships: (i) the switching between the agonist and the antagonist modes of action upon lengthening the chain between the distal acidic group and the amino acid moiety, (ii) the preference for the methyl group attached to the alpha-amino group of ligands, (iii) the preference for the D-configuration of agonists and antagonists, and (iv) the existence of "superacidic" agonists.
Tikhonova
Irina G
IG
Department of Chemistry, Moscow State University, Moscow 119992, Russia.
Baskin
Igor I
II
Palyulin
Vladimir A
VA
Zefirov
Nikolai S
NS
Bachurin
Sergey O
SO
D000595:Amino Acid Sequence; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry; D018698:Glutamic Acid / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid