Selective agonist binding of (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) and 2S-(2alpha,3beta,4beta)-2-carboxy-4-(1-methylethenyl)-3-pyrrolidineacetic acid (kainate) receptors: a molecular modeling study.
Molecular models were constructed, using the published X-ray structure of rat glutamate receptor 2 (GluR2), for the ligand-binding domains of the human (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA)- and kainate-selective ionotropic glutamate receptors (iGluRs): GluR1-7 and KA1-2. Based on the analysis of the known X-ray structures of GluR2 in complex with glutamate, kainate, and AMPA, we have constructed binding motifs (relative positioning of a ligand in the binding site and the physico-chemical interactions that take place) for selected agonist ligands and found explanations for ligand-binding selectivity to homomeric receptors among the different iGluRs. Even a single sequence difference can explain significant differences in ligand-binding affinities between two receptors. In total, there are seven residues surrounding the binding cavity that affect agonist selectivity: in GluR2, these residues are Pro478, Thr480, Leu650, Ser654, Thr686, Tyr702, and Met708. Each of these seven positions has been shown, or is predicted, to influence the presence of one or more water molecules that, when present, may form bridging hydrogen bonds between particular ligands and receptors. By using this knowledge it should be possible to design new selective agonist ligands with high affinity for any AMPA/kainate receptor.
Pentikäinen
Olli T
OT
Department of Biochemistry and Pharmacy, Abo Akademi University, Tykistökatu 6A, FIN-20520 Turku, Finland.
Settimo
Luca
L
Keinänen
Kari
K
Johnson
Mark S
MS
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018690:Excitatory Amino Acid Agonists / Q000737:chemistry / Q000494:pharmacology*; D007608:Kainic Acid / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D051381:Rats; D018091:Receptors, AMPA / Q000819:agonists; D017470:Receptors, Glutamate / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000737:chemistry / Q000378:metabolism; D000097806:GluK2 Kainate Receptor; D000097808:GluK3 Kainate Receptor
D018690:Excitatory Amino Acid Agonists; D007608:Kainic Acid; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000097806:GluK2 Kainate Receptor; D000097808:GluK3 Kainate Receptor