STRUCTURE OF A GLUTAMATE RECEPTOR BINDING DOMAIN

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Glutamate receptors are the major excitatory neurotransmitter receptors in vertebrate brain and are involved in a variety of normal and pathological neuronal functions. These proteins function by binding glutamate in an extracellular domain and opening an intrinsic ion channel that allows cations to flow in and out of the neuron. Drugs targeted to glutamate receptors may have considerable potential for treating such diverse disorders as epilepsy, amyotrophic lateral sclerosis, and ischemic brain damage. We are studying two important glutamate receptors (GluR2 and GluR3), using X-ray crystallography and NMR and ESR spectroscopy to understand the structure and dynamics and to compare the results with the function of the protein measured using single channel recording (measurement of ion conductance across the cell membrane). The structural work is done on the extracellular ligand-binding domains of the proteins (GluR2 S1S2 and GluR3 S1S2), which are a soluble constructs derived from the full-length proteins. The proteins have a bilobed structure with the binding site for glutamate and derivatives at the interface between the two lobes. For GluR2, previous work has suggested that the degree to which the lobes close upon binding of ligand may relate to the function of the protein. Our initial work with NMR spectroscopy and our recent crystal structures, suggest that the relationship between structure and function may be more complicated, involving protein flexibility. Obtaining additional structures, under conditions that reveal the range of possible motions, is essential for understanding the functional consequences of agonist binding.