Contents

Conotoxin

Group of neurotoxins

This article is missing information about genetic and architectural classification (ConoServer and PMC4278219). Please expand the article to include this information. Further details may exist on the talk page. (April 2019)

Alpha conotoxin precursor
α-Conotoxin PnIB from C. pennaceus, disulfide bonds shown in yellow. From the University of Michigan's Orientations of Proteins in Membranes database, PDB: 1AKG​.
Identifiers
Symbol	Toxin_8
Pfam	PF07365
InterPro	IPR009958
PROSITE	PDOC60004
SCOP2	1mii / SCOPe / SUPFAM
OPM superfamily	148
OPM protein	1akg
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Omega conotoxin
Schematic diagram of the three-dimensional structure of ω-conotoxin MVIIA (ziconotide). Disulfide bonds are shown in gold. From PDB: 1DW5​.
Identifiers
Symbol	Conotoxin
Pfam	PF02950
InterPro	IPR004214
SCOP2	2cco / SCOPe / SUPFAM
OPM superfamily	112
OPM protein	1fyg
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Aconotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus Conus.

Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. Conotoxins have a variety of mechanisms of actions, most of which have not been determined. However, it appears that many of these peptides modulate the activity of ion channels.^[1] Over the last few decades conotoxins have been the subject of pharmacological interest.^[2]

The LD₅₀ of conotoxin ranges from 5-25 μg/kg.^[3][4][5]

Hypervariability[edit]

Conotoxins are hypervariable even within the same species. They do not act within a body where they are produced (endogenously) but act on other organisms.^[6] Therefore, conotoxin genes experience less selection against mutations (like gene duplication and nonsynonymous substitution), and mutations remain in the genome longer, allowing more time for potentially beneficial novel functions to arise.^[7] Variability in conotoxin components reduces the likelihood that prey organisms will develop resistance; thus cone snails are under constant selective pressure to maintain polymorphism in these genes because failing to evolve and adapt will lead to extinction (Red Queen hypothesis).^[8]

Disulfide connectivities[edit]

Types of conotoxins also differ in the number and pattern of disulfide bonds.^[9] The disulfide bonding network, as well as specific amino acids in inter-cysteine loops, provide the specificity of conotoxins.^[10]

Types and biological activities[edit]

The number of conotoxins whose activities have been determined so far is five, and they are called the α(alpha)-, δ(delta)-, κ(kappa)-, μ(mu)-, and ω(omega)- types. Each of the five types of conotoxins attacks a different target:

• α-conotoxin inhibits nicotinic acetylcholine receptorsatnerves and muscles.^[11]
• δ-conotoxin inhibits fast inactivation of voltage-dependent sodium channels.^[12]
• κ-conotoxin inhibits potassium channels.^[13]
• μ-conotoxin inhibits voltage-dependent sodium channels in muscles.^[14]
• ω-conotoxin inhibits N-type voltage-dependent calcium channels.^[15] Because N-type voltage-dependent calcium channels are related to algesia (sensitivity to pain) in the nervous system, ω-conotoxin has an analgesic effect: the effect of ω-conotoxin M VII A is 100 to 1000 times that of morphine.^[16] Therefore, a synthetic version of ω-conotoxin M VII A has found application as an analgesic drug ziconotide (Prialt).^[17]

Alpha[edit]

Alpha conotoxins have two types of cysteine arrangements,^[18] and are competitive nicotinic acetylcholine receptor antagonists.

Delta, kappa, and omega[edit]

Omega, delta and kappa families of conotoxins have a knottin or inhibitor cystine knot scaffold. The knottin scaffold is a very special disulfide-through-disulfide knot, in which the III-VI disulfide bond crosses the macrocycle formed by two other disulfide bonds (I-IV and II-V) and the interconnecting backbone segments, where I-VI indicates the six cysteine residues starting from the N-terminus. The cysteine arrangements are the same for omega, delta and kappa families, even though omega conotoxins are calcium channel blockers, whereas delta conotoxins delay the inactivation of sodium channels, and kappa conotoxins are potassium channel blockers.^[9]

Mu[edit]

Mu-conotoxin
nmr solution structure of piiia toxin, nmr, 20 structures
Identifiers
Symbol	Mu-conotoxin
Pfam	PF05374
Pfam clan	CL0083
InterPro	IPR008036
SCOP2	1gib / SCOPe / SUPFAM
OPM superfamily	112
OPM protein	1ag7
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Mu-conotoxins have two types of cysteine arrangements, but the knottin scaffold is not observed.^[19] Mu-conotoxins target the muscle-specific voltage-gated sodium channels,^[9] and are useful probes for investigating voltage-dependent sodium channels of excitable tissues.^[19][20] Mu-conotoxins target the voltage-gated sodium channels, preferentially those of skeletal muscle,^[21] and are useful probes for investigating voltage-dependent sodium channels of excitable tissues.^[22]

Different subtypes of voltage-gated sodium channels are found in different tissues in mammals, e.g., in muscle and brain, and studies have been carried out to determine the sensitivity and specificity of the mu-conotoxins for the different isoforms.^[23]

See also[edit]

• Conolidine
• Contryphan, members of "conotoxin O2"
• Conantokins, also known as "conotoxin B"

References[edit]

External links[edit]

• Conotoxins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Baldomero "Toto" Olivera's Short Talk. "Conus Peptides".
• Kaas Q, Westermann JC, Halai R, Wang CK, Craik DJ. "ConoServer". Institute of Molecular Bioscience, The University of Queensland, Australia. Retrieved 2009-06-02. A database for conopeptide sequences and structures