Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Dynamics of AMPA-subtype Glutamate Receptor using Elastic Network Models
Ionotropic glutamate receptors (iGLURs) are known to mediate several excitatory neurotransmission in the central nervous system. These receptors are ligand gated ion channels that couple agonist binding to a ligand binding core, to open and desensitize the ion channel. Dysfunction of iGLURs due to injury or other stimuli, results in acute neurological disorders attracting the attention of pharmaceutical industry to iGLURs as potential drug discovery targets. The recent structure of the intact α-amino-3-hydroxy-5-methyl-4-isozazole propionic acid (AMPA) receptor (1) paved the way for a structural analysis of the dynamics of the receptor. Global, large-scale, co-operative motions of the structure are obtained using the well know Gaussian Network Model (GNM) and Anistropic Network Model (ANM) (2,3). The slowmodes within this model, enabled identification of hinge residues at the N-terminal domain (NTD), Ligand Binding domain (LBD) and at the Transmembrane Domain (TMD). The Markovian Stochastic Model (MSM) (4), enabled the identification of several key residues with low-commute times. The residues identified as hot-spots by MSM and the hinge residues identifed by GNM and ANM although scattered in the different domains, are located at structurally 'strategic' places such as NTD/LBD interface, LBD/TMD interface or even the linker region. Several of these residues are also highly conserved among the iGLUR family, and are thus anticipated to play a role in the signal transduction machinery of the AMPA-receptor.
University of Pittsburgh, Department of Computational and Systems Biology, Fifth Avenue, 3501, Biomedical Science Tower-3, Pittsburgh PA 15213