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 have a wide range of specificities for different subtypes of the voltage-sensitive calcium channel (VSCC). To understand their VSCC subtype differentiation we studied the structure of two naturally occurring omega-conotoxins, MVIIA (specific to N-type) and SVIB (specific to P/Q-type) and a synthetic hybrid, SNX-202, which has altered specificities to both VSCC subtypes. The secondary structures of the three peptides are almost identical, consisting of a triple-stranded beta-sheet and several turns. A comparison of NMR data emphasizes the structural similarities between the peptides and highlights some minor structural differences. In the three-dimensional structures of SVIB and MVIIA these are manifested as orientational differences between two key loops. The structural rigidity of MVIIA was also examined. H alpha shifts are similar in a range of solvents, indicating that there are no solvent-induced changes in structure. The omega-conotoxins form a consensus structure 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 conferred by the positions of functional side-chains on the surface of the peptides.
Centre for Drug Design and Development, University of Queensland, Brisbane, Australia.
K J
KJ
Nielsen
L
L
Thomas
R J
RJ
Lewis
P F
PF
Alewood
D J
DJ
Craik
D000595:Amino Acid Sequence; D015220:Calcium Channels / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D020960:omega-Conotoxins
D015220:Calcium Channels; D010455:Peptides; C102257:SNX 202; D020960:omega-Conotoxins; C077380:omega-conotoxin SVIB; C078452:ziconotide