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Loop Distribution

The position of the cysteine residues within the conotoxin sequence determines the disulphide linkages, and therefore the tertiary structure of the peptide. These disulphide linkages result in the formation of 'loops' of peptide sequence, and the peptide toxins can be classified according to the number of loops that they contain.

2-loop structure

seq = cc..(1)..c..(2)..c

Examples of this structure ; the alpha conotoxins

(C. geographus, C. striatus)

The primary structure of a-conotoxins consists of a single polypeptide chain less than 20 amino acids long. The main chain is restricted by two disufide bonds, which constrains the peptide into a folded state despite its very small size. The covalent structure of a-conotoxins can be shown schematically as follows:

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The disulfide bonds between the first and third cysteines and between the second and fourth cysteine confines the covalent structure to a bicyclic moiety with Loop1 as a common segment between the cyclic rings. The length of the first and second loops determines the particular subclass of a-conotoxin (Cartier et al J. Biol. Chem. 271: 7522, 1996), and their designation is anL1/nL2, where nL1 and nL2 are the lengthts of loops 1 and 2, respectively. The best characterized a-conotoxin, isolated from Conus geographus, the a-conotoxin GI (ECCNPACGRHYSC), is an a3/5-conotoxin which targets the muscle-type nicotinic receptor at the neuromuscular junction. a-conotoxin EI (RDOCCYHPTCNMSNPQIC) is an 18-residue peptide isolated from the venom of Conus ermineus, the only fish-hunting cone snail in the Atlantic Ocean, and is an a4/7-conotoxin that targets the nicotinic acetylcholine receptor found in mammalian skeletal muscle and the electric organ Torpedo. All the other a4/7-conotoxins with known 3D structure specifically target the neuronal nicotinic receptor, eg.a-conotoxin PnIA (GCCSLPPCAANNPDYC), isolated from Conus pennaceus, is an a4/7-conotoxin that targets the neuronal-type nicotinic receptor in neuronal cells. The difference in specificity among these a4/7-conotoxins that have the same structural framework can be attributed to shape, charge distribution and hydrophobicity displayed by these neuropeptides (see Franco, A. and Mari, F. Letters in Peptide Science 6: 199-207, 1999).

3-loop structure

seq = cc...(1)...c...(2)...c...(3)...c

Examples of this structure ; mu-conotoxins

(C. geographus, C. textile, Scratcher Peptide)

4-loop structure

seq = c...(1)...c...(2)

Examples of this structure ; omega-conotoxins

(C. geographus, C. magus, C. textile, the King-Kong peptide )

This structure is the most common having been identified in over 20 conotoxin peptides.

CG and BGL, June-95; revised November 2001, BGL

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