Microsecond-to-Millisecond Conformational Dynamics Demarcate the GluR2 Glutamate Receptor Bound to Agonists Glutamate, Quisqualate, and AMPA Export

@article{citeulike:2570700, abstract = {Abstract: Chemical shift changes and internal motions on microsecond-to-millisecond time scales of the S1S2 ligand-binding domain of the GluR2 ionotropic glutamate receptor have been studied by NMR spectroscopy in the presence of the agonists glutamic acid (glutamate), quisqualic acid (quisqualate), and -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). Although the crystal structures of the three agonist-bound forms of GluR2 S1S2 ligand-binding domain are very similar, chemical shift changes imply that AMPA-bound GluR2 S1S2 is conformationally distinct from glutamate- and quisqualate-bound forms of GluR2 S1S2. NMR spin relaxation measurements for backbone amide 15N nuclei reveal that GluR2 S1S2 exhibits reduced chemical exchange line broadening, resulting from microsecond-to-millisecond conformational dynamics, in AMPA-bound compared to glutamate- and quisqualate-bound states. The largest changes in line broadening are observed for two regions of GluR2 S1S2: Val683 and the segment around Lys716-Cys718. The differences in binding affinity of these agonists do not explain the differences in microsecond-to-millisecond conformational dynamics because quisqualate and AMPA bind with similar affinities that are 10-fold greater than the affinity of glutamate. Differences in conformational mobility may reflect differences in the binding mode of AMPA in the GluR2 S1S2 active site compared to the other two ligands. The sites of conformational mobility in GluR2 S1S2 imply that subtle differences exist between the agonists glutamate, quisqualate, and AMPA in modulating glutamate receptor function.}, address = {Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168th Street, New York, New York 10032}, author = {Valentine, E. R. and Palmer, A. G.}, citeulike-article-id = {2570700}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/bi047984f}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/bi047984f}, day = {8}, doi = {10.1021/bi047984f}, journal = {Biochemistry}, keywords = {dynamics, ion\_channels, md}, month = {March}, number = {9}, pages = {3410--3417}, posted-at = {2008-07-20 15:33:56}, priority = {2}, title = {Microsecond-to-Millisecond Conformational Dynamics Demarcate the GluR2 Glutamate Receptor Bound to Agonists Glutamate, Quisqualate, and AMPA}, url = {http://dx.doi.org/10.1021/bi047984f}, volume = {44}, year = {2005} }

TY - JOUR ID - citeulike:2570700 L3 - citeulike-article-id:2570700 N2 - Abstract: Chemical shift changes and internal motions on microsecond-to-millisecond time scales of the S1S2 ligand-binding domain of the GluR2 ionotropic glutamate receptor have been studied by NMR spectroscopy in the presence of the agonists glutamic acid (glutamate), quisqualic acid (quisqualate), and -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). Although the crystal structures of the three agonist-bound forms of GluR2 S1S2 ligand-binding domain are very similar, chemical shift changes imply that AMPA-bound GluR2 S1S2 is conformationally distinct from glutamate- and quisqualate-bound forms of GluR2 S1S2. NMR spin relaxation measurements for backbone amide 15N nuclei reveal that GluR2 S1S2 exhibits reduced chemical exchange line broadening, resulting from microsecond-to-millisecond conformational dynamics, in AMPA-bound compared to glutamate- and quisqualate-bound states. The largest changes in line broadening are observed for two regions of GluR2 S1S2: Val683 and the segment around Lys716-Cys718. The differences in binding affinity of these agonists do not explain the differences in microsecond-to-millisecond conformational dynamics because quisqualate and AMPA bind with similar affinities that are 10-fold greater than the affinity of glutamate. Differences in conformational mobility may reflect differences in the binding mode of AMPA in the GluR2 S1S2 active site compared to the other two ligands. The sites of conformational mobility in GluR2 S1S2 imply that subtle differences exist between the agonists glutamate, quisqualate, and AMPA in modulating glutamate receptor function. IS - 9 JF - Biochemistry AD - Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168th Street, New York, New York 10032 EP - 3417 TI - Microsecond-to-Millisecond Conformational Dynamics Demarcate the GluR2 Glutamate Receptor Bound to Agonists Glutamate, Quisqualate, and AMPA VL - 44 SP - 3410 KW - dynamics KW - ion_channels KW - md AU - Valentine, ER AU - Palmer, AG PY - 2005/03/08/ UR - http://dx.doi.org/10.1021/bi047984f ER -