N-methyl-D-aspartate (NMDA) type glutamate receptors (NMDAR)s make possible the cognitive functions of learning and memory in humans. Specific antagonists are critically needed to dissect molecular roles of NMDARs and to block hyperactivity associated with neurological diseases such as Alzheimer's, multiple sclerosis, and neuropathic pain. Newly discovered toxins derived from the venoms of marine snails (Conus and Turridae) may hold the key. These toxins can distinguish among highly related NMDARs, inhibiting one subtype but leaving others functional -- exactly the molecular properties needed for basic neurobiological research tools and pharmacologically useful compounds. We wish to determine the structures of these toxins, both as free compounds and as complexed with relevant portions of NMDA receptors. Together with binding specificity analysis (measured by isothermal titration calorimetry and other solution based methods), these structures will aid in the design of NMDAR-targeted drugs.
NMDAR-targeted toxins. (a) Conantokins are rich in gamma-carboxyglutamatic acid residues (red ovals) and adopt helical structure coupled with calcium ion binding. (b, c) Calcium ions additionally bridge toxin to the cell membrane, which probably aids in locating NMDARs. The current goals are to express ligand-binding domains derived from different NMDAR subtypes (extracellular clam-shell shapes), demonstrate subtype selectivity, and crystallize complexes with toxin.
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