conotoxins

Summary

Summary: Peptide neurotoxins from the marine fish-hunting snails of the genus CONUS. They contain 13 to 29 amino acids which are strongly basic and are highly cross-linked by disulfide bonds. There are three types of conotoxins, omega-, alpha-, and mu-. OMEGA-CONOTOXINS inhibit voltage-activated entry of calcium into the presynaptic membrane and therefore the release of ACETYLCHOLINE. Alpha-conotoxins inhibit the postsynaptic acetylcholine receptor. Mu-conotoxins prevent the generation of muscle action potentials. (From Concise Encyclopedia Biochemistry and Molecular Biology, 3rd ed)

Top Publications

  1. Buczek O, Wei D, Babon J, Yang X, Fiedler B, Chen P, et al. Structure and sodium channel activity of an excitatory I1-superfamily conotoxin. Biochemistry. 2007;46:9929-40 pubmed
    ..Thus, there is a convergence of structure and function in iota-RXIA, as its disulfide pairing and structure resemble those of funnel web spider toxins that also target sodium channels. ..
  2. Olivera B, Quik M, Vincler M, McIntosh J. Subtype-selective conopeptides targeted to nicotinic receptors: Concerted discovery and biomedical applications. Channels (Austin). 2008;2:143-52 pubmed
    ..to uncover subtype-specific ligands, called "concerted discovery"; this was applied to the alpha-conotoxins, a family of Conus peptides generally targeted to nAChRs...
  3. Prashanth J, Lewis R, Dutertre S. Towards an integrated venomics approach for accelerated conopeptide discovery. Toxicon. 2012;60:470-7 pubmed publisher
    Conopeptides and conotoxins are small peptides produced by cone snails as a part of their predatory/defense strategies that target key ion channels and receptors in the nervous system...
  4. Kelley W, Schulz J, Jakubowski J, Gilly W, Sweedler J. Two toxins from Conus striatus that individually induce tetanic paralysis. Biochemistry. 2006;45:14212-22 pubmed
    ..These effects apparently involve modification of voltage-gated sodium channels in motor axons. Notably, application of either s4a or s4b alone mimics the biological effects of the whole injected venom on fish prey. ..
  5. Lewis R, Dutertre S, Vetter I, Christie M. Conus venom peptide pharmacology. Pharmacol Rev. 2012;64:259-98 pubmed publisher
    ..potential of cone snail venom peptide families acting at voltage-gated ion channels (?-, ?-, ?O-, ?-, ?-, and ?-conotoxins), ligand-gated ion channels (?-conotoxins, ?-conotoxin, ikot-ikot, and conantokins), G-protein-coupled receptors ..
  6. Platt R, Han T, Green B, Smith M, Skalicky J, Gruszczynski P, et al. Stapling mimics noncovalent interactions of ?-carboxyglutamates in conantokins, peptidic antagonists of N-methyl-D-aspartic acid receptors. J Biol Chem. 2012;287:20727-36 pubmed publisher
    ..Our results extend the applications of peptide stapling to helical peptides with extracellular targets and provide a means for engineering conantokins with improved pharmacological properties. ..
  7. Raffa R. Diselenium, instead of disulfide, bonded analogs of conotoxins: novel synthesis and pharmacotherapeutic potential. Life Sci. 2010;87:451-6 pubmed publisher
    The venoms of the cone snail (Conus) contain toxic peptides (conotoxins) that have remarkable selectivity for subtypes of a variety of mammalian voltage- and ligand-gated ion channels, G protein-coupled receptors, and neurotransmitter ..
  8. Gowd K, Dewan K, Iengar P, Krishnan K, Balaram P. Probing peptide libraries from Conus achatinus using mass spectrometry and cDNA sequencing: identification of delta and omega-conotoxins. J Mass Spectrom. 2008;43:791-805 pubmed publisher
    ..1 to Ac 6.5) as delta, omega, and omega-like conotoxins. The presence of these predicted peptides in crude venom was established by direct matrix assisted laser ..
  9. Azam L, Yoshikami D, McIntosh J. Amino acid residues that confer high selectivity of the alpha6 nicotinic acetylcholine receptor subunit to alpha-conotoxin MII[S4A,E11A,L15A]. J Biol Chem. 2008;283:11625-32 pubmed publisher
    ..Similar effects were seen with other alpha6-selective conotoxins, suggesting the general importance of thesealpha6 residues in conferring selective binding.

More Information

Publications62

  1. Kaas Q, Yu R, Jin A, Dutertre S, Craik D. ConoServer: updated content, knowledge, and discovery tools in the conopeptide database. Nucleic Acids Res. 2012;40:D325-30 pubmed publisher
  2. Duda T, Remigio E. Variation and evolution of toxin gene expression patterns of six closely related venomous marine snails. Mol Ecol. 2008;17:3018-32 pubmed publisher
    ..show amazing levels of interspecific diversity and are comprised of a cocktail of peptide neurotoxins, termed conotoxins, that are encoded by large gene families...
  3. Zhangsun D, Luo S, Wu Y, Zhu X, Hu Y, Xie L. Novel O-superfamily conotoxins identified by cDNA cloning from three vermivorous Conus species. Chem Biol Drug Des. 2006;68:256-65 pubmed
    The O-superfamily of conotoxins includes several subfamilies with different pharmacological targets, all of which are voltage-gated ion channels and distributed widely in varied Conus species...
  4. Pi C, Liu J, Peng C, Liu Y, Jiang X, Zhao Y, et al. Diversity and evolution of conotoxins based on gene expression profiling of Conus litteratus. Genomics. 2006;88:809-819 pubmed publisher
    ..derived from a Conus litteratus venom duct was analyzed to illuminate the diversity and evolution mechanism of conotoxins. Nearly half of these ESTs represent the coding sequences of conotoxins, which were grouped into 42 novel ..
  5. Marx U, Daly N, Craik D. NMR of conotoxins: structural features and an analysis of chemical shifts of post-translationally modified amino acids. Magn Reson Chem. 2006;44 Spec No:S41-50 pubmed
    b>Conotoxins are small conformationally constrained peptides found in the venom of marine snails of the genus Conus...
  6. Luo S, Christensen S, Zhangsun D, Wu Y, Hu Y, Zhu X, et al. A novel inhibitor of ?9?10 nicotinic acetylcholine receptors from Conus vexillum delineates a new conotoxin superfamily. PLoS ONE. 2013;8:e54648 pubmed publisher
    b>Conotoxins (CTxs) selectively target a range of ion channels and receptors, making them widely used tools for probing nervous system function...
  7. Kuzmin A, Jerlhag E, Liljequist S, ENGEL J. Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior. Psychopharmacology (Berl). 2009;203:99-108 pubmed publisher
    ..Our observations support the working hypothesis that systemically active selective ligands for nAChR alpha(3)beta(2)*, beta(3), and/or alpha(6)* receptor subunits might be of therapeutic value for the treatment of alcoholism. ..
  8. Halai R, Clark R, Nevin S, Jensen J, Adams D, Craik D. Scanning mutagenesis of alpha-conotoxin Vc1.1 reveals residues crucial for activity at the alpha9alpha10 nicotinic acetylcholine receptor. J Biol Chem. 2009;284:20275-84 pubmed publisher
    ..These findings provide valuable insight into the interaction of Vc1.1 with the alpha9alpha10 nAChR subtype and will help in the further development of analogs of Vc1.1 as analgesic drugs. ..
  9. Pavlov E, Britvina T, McArthur J, Ma Q, Sierralta I, Zamponi G, et al. Trans-channel interactions in batrachotoxin-modified skeletal muscle sodium channels: voltage-dependent block by cytoplasmic amines, and the influence of mu-conotoxin GIIIA derivatives and permeant ions. Biophys J. 2008;95:4277-88 pubmed publisher
    External mu-conotoxins and internal amine blockers inhibit each other's block of voltage-gated sodium channels...
  10. Teichert R, Lopez Vera E, Gulyas J, Watkins M, Rivier J, Olivera B. Definition and characterization of the short alphaA-conotoxins: a single residue determines dissociation kinetics from the fetal muscle nicotinic acetylcholine receptor. Biochemistry. 2006;45:1304-12 pubmed
    We report the definition and characterization of a conotoxin subfamily, designated the short alphaA-conotoxins (alphaA(S)) and demonstrate that all of these share the unique property of selectively antagonizing the fetal subtype of the ..
  11. Puillandre N, Watkins M, Olivera B. Evolution of Conus peptide genes: duplication and positive selection in the A-superfamily. J Mol Evol. 2010;70:190-202 pubmed publisher
    A remarkable diversity of venom peptides is expressed in the genus Conus (known as "conotoxins" or "conopeptides")...
  12. Buczek O, Jimenez E, Yoshikami D, Imperial J, Watkins M, Morrison A, et al. I(1)-superfamily conotoxins and prediction of single D-amino acid occurrence. Toxicon. 2008;51:218-29 pubmed
    ..We previously described three I(1)-conotoxins, iota-RXIA (formerly designated r11a), r11b and r11c, each containing a d-amino acid at the third position from ..
  13. Peng C, Wu X, Han Y, Yuan D, Chi C, Wang C. Identification of six novel T-1 conotoxins from Conus pulicarius by molecular cloning. Peptides. 2007;28:2116-24 pubmed
    Cone snails are a group of ancient marine gastropods with highly sophisticated defense and prey strategies using conotoxins in their venom. Conotoxins are a diverse array of small peptides, mostly with multiple disulfide bridges...
  14. Kauferstein S, Porth C, Kendel Y, Wunder C, Nicke A, Kordis D, et al. Venomic study on cone snails (Conus spp.) from South Africa. Toxicon. 2011;57:28-34 pubmed publisher
    ..Phylogenetic analysis of the 16S RNA from numerous Conus species has clarified the evolutionary position of endemic South African Conus species and provided the first evidence for their close genetic relationships. ..
  15. Muttenthaler M, Akondi K, Alewood P. Structure-activity studies on alpha-conotoxins. Curr Pharm Des. 2011;17:4226-41 pubmed
    b>Conotoxins are small bioactive highly structured peptides from the venom of marine cone snails (genus Conus)...
  16. Franco A, Pisarewicz K, Moller C, Mora D, Fields G, Mari F. Hyperhydroxylation: a new strategy for neuronal targeting by venomous marine molluscs. Prog Mol Subcell Biol. 2006;43:83-103 pubmed
    ..we present a differential hydroxylation strategy that affects the neuronal targeting of a new set of a-conotoxins, mini-M conotoxins, conophans, and y-hydroxyconophans...
  17. Han Y, Wang Q, Jiang H, Liu L, Xiao C, Yuan D, et al. Characterization of novel M-superfamily conotoxins with new disulfide linkage. FEBS J. 2006;273:4972-82 pubmed
    The M-superfamily with the typical Cys framework (-CC-C-C-CC-) is one of the seven major superfamilies of conotoxins found in the venom of cone snails...
  18. Knapp O, McArthur J, Adams D. Conotoxins targeting neuronal voltage-gated sodium channel subtypes: potential analgesics?. Toxins (Basel). 2012;4:1236-60 pubmed publisher
    ..VGSCs have specific binding sites for four conotoxin families: ?-, ?O-, ?- and ?-conotoxins. Various studies have identified that the binding site of these peptide toxins is restricted to well-defined ..
  19. Ellison M, Haberlandt C, Gómez Casati M, Watkins M, Elgoyhen A, McIntosh J, et al. Alpha-RgIA: a novel conotoxin that specifically and potently blocks the alpha9alpha10 nAChR. Biochemistry. 2006;45:1511-7 pubmed
  20. Chen P, Dendorfer A, Finol Urdaneta R, Terlau H, Olivera B. Biochemical characterization of kappaM-RIIIJ, a Kv1.2 channel blocker: evaluation of cardioprotective effects of kappaM-conotoxins. J Biol Chem. 2010;285:14882-9 pubmed publisher
    ..2 alpha-subunit rather than antagonism to Kv1.2 homotetramers. Furthermore, kappaM-RIIIK and kappaM-RIIIJ provide a valuable set of probes for understanding the underlying mechanism of cardioprotection. ..
  21. Davis J, Jones A, Lewis R. Remarkable inter- and intra-species complexity of conotoxins revealed by LC/MS. Peptides. 2009;30:1222-7 pubmed publisher
    ..Given this inherent diversity and variability, more sensitive bioassays and sequencing techniques will be required to fully explore conotoxin bioactivity. ..
  22. Luo S, Zhangsun D, Zhu X, Wu Y, Hu Y, Christensen S, et al. Characterization of a novel ?-conotoxin TxID from Conus textile that potently blocks rat ?3?4 nicotinic acetylcholine receptors. J Med Chem. 2013;56:9655-63 pubmed publisher
    ..CTx TxID is a novel tool with which to probe the structure and function of ?3?4 nAChRs. ..
  23. Zamora Bustillos R, Aguilar M, Falcón A, Heimer de la Cotera E. Identification, by RT-PCR, of four novel T-1-superfamily conotoxins from the vermivorous snail Conus spurius from the Gulf of Mexico. Peptides. 2009;30:1396-404 pubmed publisher
    ..From it, PCR products were generated, sequenced, and predicted to encode eight distinct precursors of T-1-conotoxins. These precursors contain five different mature toxins, of which four are novel and one (sr5a) has been ..
  24. Walewska A, Zhang M, Skalicky J, Yoshikami D, Olivera B, Bulaj G. Integrated oxidative folding of cysteine/selenocysteine containing peptides: improving chemical synthesis of conotoxins. Angew Chem Int Ed Engl. 2009;48:2221-4 pubmed publisher
  25. Dutertre S, Lewis R. Toxin insights into nicotinic acetylcholine receptors. Biochem Pharmacol. 2006;72:661-70 pubmed
    ..nicotinic acetylcholine receptors (nAChRs), the subtype specific snake alpha-neurotoxins and cone snail alpha-conotoxins have been widely used to probe receptor structure and function in native tissues and recombinant systems...
  26. Westermann J, Clark R, Craik D. Binding mode of alpha-conotoxins to an acetylcholine binding protein determined by saturation transfer difference NMR. Protein Pept Lett. 2008;15:910-4 pubmed
    The saturation transfer difference (STD) NMR technique was employed to study the complex of the alpha-conotoxins Vc1...
  27. Luo S, Zhangsun D, Feng J, Wu Y, Zhu X, Hu Y. Diversity of the O-superfamily conotoxins from Conus miles. J Pept Sci. 2007;13:44-53 pubmed
    ..Remarkable sequence diversity of O-superfamily conotoxins was found in a worm-hunting cone snail Conus miles...
  28. Cnudde S, Prorok M, Dai Q, Castellino F, Geiger J. The crystal structures of the calcium-bound con-G and con-T[K7gamma] dimeric peptides demonstrate a metal-dependent helix-forming motif. J Am Chem Soc. 2007;129:1586-93 pubmed
    ..This represents a new paradigm in helix stabilization completely independent of the hydrophobic effect, which we define as the "metallo-zipper." ..
  29. Whiteaker P, Christensen S, Yoshikami D, Dowell C, Watkins M, Gulyas J, et al. Discovery, synthesis, and structure activity of a highly selective alpha7 nicotinic acetylcholine receptor antagonist. Biochemistry. 2007;46:6628-38 pubmed
    ..Structure-activity information regarding conotoxins from distantly related Conus species was employed to modify the C...
  30. Blanchfield J, Gallagher O, Cros C, Lewis R, Alewood P, Toth I. Oral absorption and in vivo biodistribution of alpha-conotoxin MII and a lipidic analogue. Biochem Biophys Res Commun. 2007;361:97-102 pubmed
    b>Conotoxins are highly constrained peptide toxins that exhibit pharmaceutically relevant biological activities...
  31. Kauferstein S, Kendel Y, Nicke A, Coronas F, Possani L, Favreau P, et al. New conopeptides of the D-superfamily selectively inhibiting neuronal nicotinic acetylcholine receptors. Toxicon. 2009;54:295-301 pubmed publisher
    ..Due to their high affinity, these new ligands may provide a tool to decipher the localisation and function of the various neuronal nAChRs. ..
  32. Chi S, Kim D, Olivera B, McIntosh J, Han K. Solution conformation of a neuronal nicotinic acetylcholine receptor antagonist alpha-conotoxin OmIA that discriminates alpha3 vs. alpha6 nAChR subtypes. Biochem Biophys Res Commun. 2006;345:248-54 pubmed
    ..are suggested by comparing its surface characteristics with other functionally related alpha4/7 subfamily conotoxins. Reduced size of the hydrophilic area in alpha-conotoxin OmIA seems to be associated with the reduced affinity ..
  33. Terrat Y, Biass D, Dutertre S, Favreau P, Remm M, Stocklin R, et al. High-resolution picture of a venom gland transcriptome: case study with the marine snail Conus consors. Toxicon. 2012;59:34-46 pubmed publisher
    ..Further comparison with proteomic and genomic data will lead to a better understanding of conopeptides diversity and the underlying mechanisms involved in conopeptide evolution. ..
  34. Glick S, Sell E, McCallum S, Maisonneuve I. Brain regions mediating ?3?4 nicotinic antagonist effects of 18-MC on nicotine self-administration. Eur J Pharmacol. 2011;669:71-5 pubmed publisher
    ..The data also suggest that an action of 18-MC in the interpeduncular nucleus may attenuate aversive and/or depressive effects of nicotine. ..
  35. McArthur J, Singh G, McMaster D, Winkfein R, Tieleman D, French R. Interactions of key charged residues contributing to selective block of neuronal sodium channels by ?-conotoxin KIIIA. Mol Pharmacol. 2011;80:573-84 pubmed publisher
    ..Recognition of these molecular determinants of KIIIA block may facilitate further development of subtype-specific, sodium channel blockers to treat hyperexcitability disorders. ..
  36. Liu Z, Yu Z, Liu N, Zhao C, Hu J, Dai Q. cDNA cloning of conotoxins with framework XII from several Conus species. Acta Biochim Biophys Sin (Shanghai). 2010;42:656-61 pubmed publisher
    In our efforts for cloning novel I(2)-superfamily conotoxins using the signal peptide sequence, we identified a novel conotoxin Lt12.4 from Conus litteratus...
  37. Xiao C, Huang Y, Dong M, Hu J, Hou S, Castellino F, et al. NR2B-selective conantokin peptide inhibitors of the NMDA receptor display enhanced antinociceptive properties compared to non-selective conantokins. Neuropeptides. 2008;42:601-9 pubmed publisher
  38. Stürzebecher A, Hu J, Smith E, Frahm S, Santos Torres J, Kampfrath B, et al. An in vivo tethered toxin approach for the cell-autonomous inactivation of voltage-gated sodium channel currents in nociceptors. J Physiol. 2010;588:1695-707 pubmed publisher
    ..This novel genetic methodology can be used for circuit mapping and has the key advantage that it enables the dissection of the contribution of specific ionic currents to neuronal function and to behaviour. ..
  39. Wang L, Pi C, Liu J, Chen S, Peng C, Sun D, et al. Identification and characterization of a novel O-superfamily conotoxin from Conus litteratus. J Pept Sci. 2008;14:1077-83 pubmed publisher
    ..The signal peptide sequence of lt6c is highly conserved in O-superfamily conotoxins and the mature peptide consists of six cysteines arranged in the pattern of C-C-CC-C-C that is defined the O-..
  40. Choudhary G, Aliste M, Tieleman D, French R, Dudley S. Docking of mu-conotoxin GIIIA in the sodium channel outer vestibule. Channels (Austin). 2007;1:344-52 pubmed
    ..This modeling also provides a set of testable predictions for toxin-channel interactions, hitherto not described, that may contribute to high-affinity binding and channel isoform selectivity. ..
  41. Klimis H, Adams D, Callaghan B, Nevin S, Alewood P, Vaughan C, et al. A novel mechanism of inhibition of high-voltage activated calcium channels by ?-conotoxins contributes to relief of nerve injury-induced neuropathic pain. Pain. 2011;152:259-66 pubmed publisher
    b>Conotoxins that are thought to act as antagonists of nicotinic acetylcholine receptors (nAChRs) containing ?3-subunits are efficacious in several preclinical models of chronic pain. Potent interactions of Vc1...
  42. Favreau P, Benoit E, Hocking H, Carlier L, D hoedt D, Leipold E, et al. A novel µ-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors. Br J Pharmacol. 2012;166:1654-68 pubmed publisher
    ..We characterized the pharmacology of a new µ-conopeptide (µ-CnIIIC) on a range of preparations and molecular targets to assess its potential as a myorelaxant...
  43. Chi S, Lee S, Kim D, Kim J, Olivera B, McIntosh J, et al. Solution structure of alpha-conotoxin PIA, a novel antagonist of alpha6 subunit containing nicotinic acetylcholine receptors. Biochem Biophys Res Commun. 2005;338:1990-7 pubmed
    ..The alpha-conotoxin PIA has an "omega-shaped" overall topology as other alpha4/7 subfamily conotoxins. Yet, unlike other neuronally targeted alpha4/7-conotoxins, its N-terminal tail Arg1-Asp2-Pro3 protrudes out of ..
  44. Daly N, Craik D. Structural studies of conotoxins. IUBMB Life. 2009;61:144-50 pubmed publisher
    b>Conotoxins are small disulfide-rich peptides from the venoms of marine cone snails...
  45. Cuny H, de Faoite A, Huynh T, Yasuda T, Berecki G, Adams D. ?-Aminobutyric acid type B (GABAB) receptor expression is needed for inhibition of N-type (Cav2.2) calcium channels by analgesic ?-conotoxins. J Biol Chem. 2012;287:23948-57 pubmed publisher
    b>Conotoxins Vc1.1 and RgIA are small peptides isolated from the venom of marine cone snails. They have effective anti-nociceptive actions in rat models of neuropathic pain...
  46. Teichert R, Jacobsen R, Terlau H, Yoshikami D, Olivera B. Discovery and characterization of the short kappaA-conotoxins: a novel subfamily of excitatory conotoxins. Toxicon. 2007;49:318-28 pubmed
    We have characterized the defining members of a novel subfamily of excitatory conotoxins, the short kappaA-conotoxins (kappaA(S)-conotoxins)...
  47. Brust A, Tickle A. High-throughput synthesis of conopeptides: a safety-catch linker approach enabling disulfide formation in 96-well format. J Pept Sci. 2007;13:133-41 pubmed
    b>Conotoxins exhibit a high degree of selectivity and potency for a range of pharmacologically relevant targets...
  48. Chang D, Duda T. Extensive and continuous duplication facilitates rapid evolution and diversification of gene families. Mol Biol Evol. 2012;29:2019-29 pubmed publisher
  49. Carstens B, Clark R, Daly N, Harvey P, Kaas Q, Craik D. Engineering of conotoxins for the treatment of pain. Curr Pharm Des. 2011;17:4242-53 pubmed
    ..In this article, we discuss structural and biological studies on several classes of conotoxins that have potential as drug leads for the treatment of pain...
  50. Van Der Haegen A, Peigneur S, Dyubankova N, Moller C, MARI F, Diego Garcia E, et al. Pc16a, the first characterized peptide from Conus pictus venom, shows a novel disulfide connectivity. Peptides. 2012;34:106-13 pubmed publisher
    ..Hence, the specific target of pc16a still remains to be discovered. ..
  51. Tayo L, Lu B, Cruz L, Yates J. Proteomic analysis provides insights on venom processing in Conus textile. J Proteome Res. 2010;9:2292-301 pubmed publisher
    ..b>Conotoxins are known to possess powerful neurological effects and some have been developed for therapeutic uses...
  52. Clark R, Daly N, Halai R, Nevin S, Adams D, Craik D. The three-dimensional structure of the analgesic alpha-conotoxin, RgIA. FEBS Lett. 2008;582:597-602 pubmed publisher
    ..We determined the three-dimensional structure of RgIA using NMR methods to assist in elucidating the molecular role of RgIA in analgesia and inflammation. ..
  53. Gupta K, Kumar M, Balaram P. Disulfide bond assignments by mass spectrometry of native natural peptides: cysteine pairing in disulfide bonded conotoxins. Anal Chem. 2010;82:8313-9 pubmed publisher
    ..This approach is illustrated by establishing cysteine pairing patterns in five conotoxins containing two disulfide bonds...