Ionotropic glutamate receptors (iGluRs) are multimeric, ligand-gated ion channels that are a major component of the central nervous system. They have been implicated in such processes as learning and memory, and a host of neurological disorders such as stroke, epilepsy, schizophrenia and Parkinson's disease have been attributed to their dysfuntion. Detailed structural studies on the isolated ligand-binding domain have suggested that conformational changes associated with agonist binding lead to the opening of the channel gate.
The aim of this proposal is to better understand the molecular mechanisms involved in channel gating, at the atomic level, by solving the crystal structure of an iGluR with the ion channel intact. Using rat GluR2 as a template, several modifications will be made in pursuit of a minimal construct that forms a stable tetrameric species in the presence of detergent and is amenable to crystallization. The data obtained in this study will greatly improve our understanding of iGluR function and may lead to the development of new, more effective therapeutics.
| Sobolevsky, Alexander I; Rosconi, Michael P; Gouaux, Eric (2009) X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462:745-56 |
