A CONSENSUS STRUCTURE FOR OMEGA-CONOTOXINS WITH DIFFERENT SELECTIVITIES FOR VOLTAGE-SENSITIVE CALCIUM-CHANNEL SUBTYPES - COMPARISON OF MVIIA, SVIB AND SNX-202

The omega-conotoxins are a set of structurally related peptides that h ave a wide range of specificities for different subtypes of the voltag e-sensitive calcium channel (VSCC). To understand their VSCC subtype d ifferentiation we studied the structure of two naturally occurring ome ga-conotoxins, MVIIA (specific to N-type) and SVIB (specific to P/Q-ty pe) and a synthetic hybrid, SNX-202, which has altered specificities t o both VSCC subtypes. The secondary structures of the three peptides a re almost identical, consisting of a triple-stranded beta-sheet and se veral turns. A comparison of NMR data emphasizes the structural simila rities between the peptides and highlights some minor structural diffe rences. Tn the three-dimensional structures of SVIB and MVIIA these ar e manifested as orientational differences between two key loops. The s tructural rigidity of MVIIA was also examined. H-alpha shifts are simi lar in a range of solvents, indicating that there are no solvent-induc ed changes in structure. The omega-conotoxins form a consensus structu re despite differences in sequence and VSCC subtype specificity. This indicates that the omega-conotoxin macrosites for the N/P/Q-subfamily of VSCCs are related, with specificity for receptor targets being conf erred by the positions of functional side-chains on the surface of the peptides. (C) 1996 Academic Press Limited