Subtype selectivity and flexibility of ionotropic glutamate receptors upon antagonist ligand binding Export

@article{citeulike:3814723, abstract = {The binding modes of a set of known ionotropic glutamate receptor antagonist-ligands have been studied using homology modeling, molecular docking, molecular dynamics (MD) simulations and ab initio quantum mechanical calculations. The core structure of the studied ligands is the decahydroisoquinoline ring, which has a carboxylic acid group at position three and different negatively-charged substituents (R) at position six. The binding affinities of these molecules have been reported earlier. From the current study, the carboxylate group of the decahydroisoquinoline ring hydrogen bonds with Arg485, the amino group with Pro478 and Thr480, and the negatively charged substituent R interacts with the positively charged N-terminus of helix-F. The subtype selectivity of these ligands seems to be strongly dependent on the amino acid at position 650 (GluR2: leucine, GluR5: valine), which affects the conformation of the ligand and ligand-receptor interactions, but depends considerably on the size of the R-group of the ligand. In addition, the MD simulations also revealed that the relative positions of the S1 and S2 domains can alter significantly showing different "closure" and "rotational movements" depending on the antagonist-ligand that is bound. Accordingly, molecular docking of antagonist ligands into static crystal structures cannot sufficiently explain ligand binding and subtype selectivity.}, author = {Pentikainen, Ulla and Settimo, Luca and Johnson, Mark S. and Pentikainen, Olli T.}, citeulike-article-id = {3814723}, citeulike-linkout-0 = {http://dx.doi.org/10.1039/b515111b}, citeulike-linkout-1 = {http://www.rsc.org/Publishing/Journals/article.asp?doi=b515111b}, doi = {10.1039/b515111b}, journal = {Org. Biomol. Chem.}, keywords = {flexibility, nmda}, number = {6}, pages = {1058--1070}, posted-at = {2008-12-20 17:12:27}, priority = {2}, publisher = {The Royal Society of Chemistry}, title = {Subtype selectivity and flexibility of ionotropic glutamate receptors upon antagonist ligand binding}, url = {http://dx.doi.org/10.1039/b515111b}, volume = {4}, year = {2006} }

TY - JOUR ID - citeulike:3814723 L3 - citeulike-article-id:3814723 N2 - The binding modes of a set of known ionotropic glutamate receptor antagonist-ligands have been studied using homology modeling, molecular docking, molecular dynamics (MD) simulations and ab initio quantum mechanical calculations. The core structure of the studied ligands is the decahydroisoquinoline ring, which has a carboxylic acid group at position three and different negatively-charged substituents (R) at position six. The binding affinities of these molecules have been reported earlier. From the current study, the carboxylate group of the decahydroisoquinoline ring hydrogen bonds with Arg485, the amino group with Pro478 and Thr480, and the negatively charged substituent R interacts with the positively charged N-terminus of helix-F. The subtype selectivity of these ligands seems to be strongly dependent on the amino acid at position 650 (GluR2: leucine, GluR5: valine), which affects the conformation of the ligand and ligand-receptor interactions, but depends considerably on the size of the R-group of the ligand. In addition, the MD simulations also revealed that the relative positions of the S1 and S2 domains can alter significantly showing different "closure" and "rotational movements" depending on the antagonist-ligand that is bound. Accordingly, molecular docking of antagonist ligands into static crystal structures cannot sufficiently explain ligand binding and subtype selectivity. IS - 6 JF - Org. Biomol. Chem. EP - 1070 TI - Subtype selectivity and flexibility of ionotropic glutamate receptors upon antagonist ligand binding PB - The Royal Society of Chemistry VL - 4 SP - 1058 KW - flexibility KW - nmda AU - Pentikainen, Ulla AU - Settimo, Luca AU - Johnson, Mark AU - Pentikainen, Olli PY - 2006/// UR - http://dx.doi.org/10.1039/b515111b ER -