3-DIMENSIONAL SOLUTION STRUCTURE OF ALPHA-CONOTOXIN MII, AN ALPHA(3)BETA(2) NEURONAL NICOTINIC ACETYLCHOLINE RECEPTOR-TARGETED LIGAND

alpha-Conotoxin MII, isolated from Conus magus, is a potent peptidic t oxin which specifically targets the mammalian neuronal nicotinic acety lcholine receptor, alpha(3) beta(2) subtype. The three-dimensional str ucture of alpha-conotoxin MII in aqueous solution has been determined by two-dimensional H-1 NMR spectroscopy. NOE-derived distances, refine d by an iterative relaxation matrix approach, as well as dihedral and chirality restraints were used in high-temperature biphasic simulated annealing calculations. Fourteen minimum energy structures out of 50 s ubjected to the SA simulations were chosen for evaluation; these 14 st ructures have a final RMS deviation of 0.76 +/- 0.31 and 1.35 +/- 0.34 Angstrom for the backbone and heavy atoms, respectively. The overall structure is unusually well-defined due to a large helical component a round the two disulfide bridges. The principal backbone folding motif may be common to a subclass of alpha-conotoxins. There are two distinc t surfaces on the molecule almost at right angles to one another. One entirely consists of the hydrophobic residues Gly(1), Cys(2), Cys(3), Leu(15), and Cys(16). The second comprises the hydrophilic residues Gl u(11), His(12), Ser(13), and Asn(14). These surfaces on the ligand cou ld be essential for the subtype-specific recognition of the receptor.