SOLUTION STRUCTURE OF OMEGA-CONOTOXIN GVIA USING 2-D NMR-SPECTROSCOPYAND RELAXATION MATRIX ANALYSIS

We report here the solution structure of omega-conotoxin GVIA, a pepti de antagonist of the N-type neuronal voltage-sensitive calcium channel . The structure was determined using two-dimensional NMR in combinatio n with distance geometry and restrained molecular dynamics. The full r elaxation matrix analysis program MARDIGRAS was used to generate maxim um and minimum distance restraints from the crosspeak intensities in N OESY spectra. The 187 restraints obtained were used in conjunction wit h 23 angle restraints from vicinal coupling constants as input for the structure calculations. The backbones of the best 21 structures match with an average pairwise RMSD of 0.58 angstrom. The structures contai n a short segment of triple-stranded beta-sheet involving residues 6-8 , 18-21, and 24-27, making this the smallest published peptide structu re to contain a triple-stranded beta-sheet. Conotoxins have been shown to be effective neuroprotective agents in animal models of brain isch emia. Our results should aid in the design of novel nonpeptide compoun ds with potential therapeutic utility.