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Publications on Conotoxins from B.M. Olivera and colleagues - (Olivera BM, Cruz LJ, Gray WR, (Emeritus), Hillyard DR, Jacobsen R, McIntosh JM, Yoshikami D., and others)

***** Complete list of Olivera's Publications 1964-2004 *****

***** List of J. Michael McIntosh's Publications 1982-2000 *****

Selected References on Cone shell toxins - most recent listed first : See also recent papers listed in "What's new for 1999; 2000 and 2001

Links to Baldomero Olivera's research within the Bioscience Program and Molecular Biology (Neurobiology). Prof. Baldomero Olivera is scientific founder of Cognetix Inc and both Prof. Olivera and Dr Lourdes Cruz are members of The Board of GeneSeas Asia Inc.


Latest addition : (Click here for publication list maintained by Olivera and colleagues at UofU Conus Web. Or here for a more comprehensive list of Olivera's references.)

Maillo, M., M.B. Aguilar, E. Lopez-Vera, A.G. Craig, G. Bulaj, B.M. Olivera and E.P. Heimer de la Cortera (2001) Conorfamide, a Conus venom peptide belonging to the RFamide family of neuropeptides. Toxicon, 40: 401-407.
Abstract: A novel Conus peptide, conorfamide-Sr1, has been characterized. The sequence of the natural peptide was determined using standard Edman sequencing methods and mass spectrometry, and confirmed by chemical synthesis. The peptide has 12 amino acids and no cysteine residues. The following sequence was obtained: GPMGWVPVFYRF-NH(2). No other peptide from a vermivorous Atlantic Conus species has previously been characterized. Conorfamide-Sr1 belongs to the RFamide neuropeptide family, and is the first RFamide peptide to be found in any venom. The presence of conorfamide-Sr1 as a major peptide in Conus spurius venom suggests that Conus lineages in the Atlantic may have evolved novel Conus venom peptide families.

Espiritu DJ, Watkins M, Dia-Monje V, Cartier GE, Cruz LJ, Olivera BM. (2001) Venomous cone snails: molecular phylogeny and the generation of toxin diversity. Toxicon, 39: 1899-1916.
Abstract: In order to investigate the generation of conotoxin diversity, delta-conotoxin sequences from nine Conus species were analyzed in the context of their phylogeny. Using a standard molecular marker, mitochondrial 16S RNA, we determined that the delta-conotoxins were derived from three distinct species clades based on the phylogenetic reconstruction of a large set (>80) of Conus species and other toxoglossate molluscs. Four different mechanisms appear to have contributed to the diversity of the delta-conotoxins analyzed: (1) Speciation: delta-Conotoxins in different species diverge from each other (the prepro regions of orthologous genes somewhat more slowly than the reference rRNA rate, the mature toxin regions significantly faster). (2) Duplication: Intraspecific delta-conotoxin divergence is initiated by gene duplication events, some of which may have predated the species itself. (3) Recombination: A novel delta-conotoxin may arise through recombination of two parental delta-contoxin genes. (4) 'Focal hypermutation': This sudden, almost saltatory change in sequence is always restricted to the mature toxin region.The first three have been recognized previously as mechanisms important for the evolution of gene families in other phylogenetic systems; the last is a remarkable, mechanistically unexplained and specialized feature of Conus peptide diversification.


Listed as "In-Press" (Jan 2002)

Espiritu, J.D., L.J. Cruz, G.E. Cartier and B.M. Olivera (2001) Venomous gastropods: Conus, conoideans and other neogastropod families. Bollettino Malacologico, in press.


Baldomero M Olivera, Lourdes J Cruz and Doju Yoshikami (1999) Effects of Conus peptides on the behavior of mice [Review article] Current Opinion in Neurobiology 9:772-777.

Craig, A. G., Norberg, T., Griffin, D., Hoeger, C., Akhtar, M., Schmidt, K., Low, W., Dykert, J., Richelson, E., Navarro, V., Mazella, J., Watkins, M., Hillyard, D., Imperial, J., Cruz, L. J., Olivera, B. M. (1999). "Contulakin-G, an O-Glycosylated Invertebrate Neurotensin" J. Biol. Chem. 274: 13752-13759.
[Contulakin-G is a 16 amino acid O-linked glycopeptide (pGlu-Ser-Glu-Glu-Gly-Gly-Ser-Asn-Ala-Thr-Lys-Lys-Pro-Tyr-Ile-Leu-OH, pGlu is pyroglutamate) from Conus geographus, whose C-terminus resembles neurotensin. Causes motor control-associated dysfunction when injected into mice. The investigators conclude "that O-linked glycosylation appears to be a highly unusual strategy for increasing the efficacy of toxins directed against neurotransmitter receptors"].

Shon, K., Olivera, B.M., Watkins, M., Jacobsen, R.B., Gray, W.R, Floresca, C.Z., Cruz, L.J., Hillyard, D.R., Brink, A., Terlau, H., Yoshikami, D. (1998) m -CTX PIIIA, a new peptide for discriminating among tetrodotoxin-sensitive Na channel subtypes. J. Neurosci 18: 4473-4481.

Bandyopadhyay, P.K., Colledge, C.J., Walker, C.S., Zhou, L., Hillyard, D.R., Olivera, B.M. (1998) Conantokin-G precursor and its role in g -carboxylation by a vitamin K-dependent carboxylase from a Conus snail. J.Biol.Chem. 273: 5447-5450.

Jacobsen, R., Yoshikami, D., D., Ellison, M., Martinez, J., Gray, W.R., Cartier, G.E., Shon, K.J., Groebe, D.R., Abramson, S.N., Olivera, B.M. and McIntosh, J.M. (1997) Differential targeting of nicotinic acetylcholine receptors by novel alphaA-conotoxins  J Biol Chem 272 (36) 22531-22537. 

Shon, K-J., Grilley, M., Jacobsen, R., Cartier, E., Hopkins, C., Gray, W.R., Watkins, M., Hillyard, D.R., Rivier, J., Torres, J., Yoshikami, D., and Olivera, B.M. (1997) A noncompetitive peptide inhibitor of the nicotinic acetylcholine receptor from Conus purpurascens venom. Biochemistry 36: 9581-9587. 

Stanley, T.B., Stafford, D.W., Olivera, B.M. and Bandyopadhyay, P.K. (1997) Identification of a vitamin K-dependent carboxylase in the venom duct of a Conus snail. FEBS Letters 407 85-88. [Abstract: Peptides from the venom ducts of cone snails (genus Conus) contain gamma-carboxyglutamate residues. The gamma-glutamyl carboxylase responsible for this post-translational modification is localized in the microsomal fraction, strictly dependent on vitamin K, activated by ammonium sulfate, and is associated with endogenous substrate. The K(m) of the enzyme for vitamin K is comparable to that for the bovine carboxylase. However, a propeptide containing substrate related to the blood coagulation protein factor IX, a highly efficient substrate for the bovine enzyme, was poorly carboxylated by the Conus enzyme, suggesting differences in gamma-carboxylase recognition signal sequences and/or structural requirements at the carboxylation site.] 

Tavazoie, S.F., Tavazoie, M.F., McIntosh, J.M., Olivera, B.M and Yoshikami, D., (1997) Differential block of nicotinic synapses on B versus C neurones in sympathetic ganglia of frog by a-conotoxins MII and ImI. Brit. J. Pharmacol. 120: 995-1000. 

Han KH, Hwang KJ, Kim SM, Kim SK, Gray WR, Olivera BM, Rivier J, Shon KJ (1997) NMR structure determination of a novel conotoxin, [Pro 7,13] alpha A-conotoxin PIVA. Biochemistry 36: 1669-1677 [Abstract: A high-resolution solution conformation of a novel conotoxin, [Pro 7,13] alpha A-conotoxin PIVA, GCCGSYPNAACHPCSCKDROSYCGQ-NH2, has been determined by two-dimensional 1H NMR methods and distance geometry calculations. The total of 324 NOE-derived interproton distance restraints including 33 long-range NOE restraints as well as 11 phi and 7 chi 1 torsion angle restraints was used for computation of structures. Back-calculation from the experimental NOE spectrum has provided 49 new NOE restraints and yielded the final R-factors of Ra = 0.641 and Rb = 0.157. The final RMSD values are 0.90 and 1.16 A for the backbone and the heavy atoms, respectively. The C-terminal half of the molecule involving the residues 12-24 is extremely well-defined with a backbone RMSD value of 0.56 A, whereas the N-terminal 3-11 disulfide loop is relatively flexible, possessing a backbone RMSD value of 1.09 A. The [Pro 7,13] alpha A-conotoxin PIVA does not contain any significant secondary structure although the 21S-24G nearly completes one turn of a 3(10) helix. The overall protein fold is largely maintained by the three disulfide bridges of 2-16, 3-11, and 14-23. The presence of the three disulfide bridges imposes geometric constraints that force the molecule to form six continuous bends involving the following residues: 3C-5S, 7P-10A, 12H-14C, 15S-17K, 17K-19R, and 21S-25Q. The overall shape of the [Pro 7,13] alpha A-conotoxin PIVA can be described as an "iron". Residues 15S-19R form a loop that protrudes out of the "bottom plate" formed by the rest of the protein and constitute the handle of the iron. The N-terminal tip of the molecule is relatively immobile due to attractive electrostatic interactions between the gamma-hydroxyl group of 20 Hyp and the phenolic hydroxyl group of 22Y. The flexible 3-11 disulfide loop consists mostly of hydrophobic residues, while the best-defined 14-23 disulfide loop contains the highly charged hydrophilic 15S-19R "handle" domain exposed to the exterior of the protein. Binding to nicotinic acetylcholine receptor can be mediated through two different types of interactions: one involving the aromatic hydrophobic residues such as 6Y and 12H and the other involving the positively charged hydrophilic side chain of the 19R. The side chain of the 19R in the [Pro 7, 13] alpha A-conotoxin PIVA and that of the 9R of the alpha-conotoxin G1, and also the side chains of the 12H and 6Y in the former and those of 10H and 11Y in the latter can be aligned to point to the same direction when the corresponding backbone atoms are superimposed to an RMSD value of 2.5 A.] 

Craig, A., Fischer,W., Rivier,J.E. McIntosh J.M.and Gray,W.R. "Mass spectrometric scanning methods applied to Conus venom" Techniques in Protein Chemistry (in press) 


Olivera, B. (1997) E.E. Just Lecture, 1996. Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology. Molecular Biology of the Cell 8: 2101-2109

Read a popular account of "Toto" Olivera's recent research in the Salt Lake Tribune, describing envenomation by the piscivorous Purple Cone, C. purpurascens, complete with photos of the mollusc immobilizing a Clown Fish.
This material is now archived here: CONE SNAILS MAY BE BEAUTIFUL, BUT THEIR ... 11/19/93 and here KILLER SNAIL UTAH ... 05/09/96 and MEDICINE FROM SNAILS.......HEALTH ... 03/07/96

Alternatively, read the scientific account in Nature below: 

Terlau, H., Shon, K-J., Grilley, M., Stocker, M., Stuhmer, W. and Olivera, B.M. (1996) Strategy for rapid immobilization of prey by a fish-hunting marine snail. Nature 381: 148-151. 

Cartier, G.E., Yoshikami, D., Gray, W.R., Luo, S., Olivera, B.M. and McIntosh, M. (1996) A new a-conotoxin which targets a3b2 nicotinic acetylcholine receptor. J. Biol. Chem. 271: 7522-7528. 

Martinez, J.S., Olivera, B.M., Gray, W.R., Craig, A.G., Groebe, D.R., Abramson, S.N. and McIntosh, J.M. (1995) a-conotoxin EI, a new nicotinic acetylcholine receptor antagonist with novel selectivity. Biochemistry 34: 14519-14526. 

Masson, A., Shon, K-J., Oliver, B.M., Spira, M.E. (1995) Alterations of voltage-activated sodium current by a novel conotoxin from the venom of Conus gloriamaris. J. Neurophysiology 73: 1295-1302. 

Olivera BM., Hillyard DR., Marsh M. and Yoshikami, D. (1995) Combinatorial peptide libraries in drug design: lessons from venomous cone snails. Trends Biotechnol 13: 422-426. 

Hopkins C., Grilley M., Miller C., Shon KJ., Cruz LJ., Gray WR., Dykert J., Rivier J., Yoshikami, D. and Olivera BM (1995) A new family of Conus peptides targeted to the nicotinic acetylcholine receptor. J Biol Chem 270: 22361-22367. 

McIntosh JM., Hasson A., Spira ME., Gray WR., Li W., Marsh M., Hillyard DR and Olivera BM (1995) A new family of conotoxins that blocks voltage-gated sodium channels. J Biol Chem 270: 16796-16802 

Shon KJ., Grilley MM., Marsh M., Yoshikami, D., Hall AR., Kurz B., Gray WR., Imperial JS., Hillyard DR and Olivera BM (1995) Purification, characterization, synthesis, and cloning of the lockjaw peptide from Conus purpurascens venom. Biochemistry 34: 4913-8.

McIntosh JM., Ghomashchi F., Gelb MH., Dooley DJ., Stoehr SJ., Giordani AB., Naisbitt SR and Olivera BM (1995) Conodipine-M, a novel phospholipase A2 isolated from the venom of the marine snail Conus magus. J Biol Chem 270: 3518-26. 

Shon, K-J., Hasson, A., Spira, M.E., Cruz L.J., Gray, W.R. and Olivera B.M. (1994) Delta-Conotoxin GmVIA, a novel peptide from the venom of Conus gloriamaris. Biochemistry 33: 11420-11425 

Filloux, F., Karras, J., Imperial, J.S., Gray W.R. and Olivera B.M. (1994) The distribution of omega-conotoxin MVIIC[nle] binding sites in rat brain measured by autoradiography" Neuroscience Letters, 178:2 263-266 

Olivera BM., Miljanich GP., Ramachandran J and Adams ME (1994) Calcium channel diversity and neurotransmitter release: the omega-conotoxins and omega-agatoxins. Annu Rev Biochem 63: 823-67.

Shon KJ., Hasson A., Spira ME., Cruz LJ., Gray WR and Olivera BM (1994) Delta-conotoxin GmVIA, a novel peptide from the venom of Conus gloriamaris. Biochemistry 33: 11420-5.

Adams ME and Olivera BM (1994) Neurotoxins: overview of an emerging research technology. Trends Neurosci 17: 151-5. 

McIntosh JM., Yoshikami, D., Mahe E., Nielsen DB., Rivier JE., Gray WR and Olivera BM (1994) A nicotinic acetylcholine receptor ligand of unique specificity, alpha-conotoxin ImI. J Biol Chem 269: 16733-16739

Monje VD., Haack JA., Naisbitt SR., Miljanich G., Ramachandran J., Nasdasdi L., Olivera BM., Hillyard DR and Gray WR (1993) A new Conus peptide ligand for Ca channel subtypes. Neuropharmacology 32: 1141-9.

Haack JA., Kinser P., Yoshikami, D. and Olivera BM (1993) Biotinylated derivatives of omega-conotoxins GVIA and MVIID: probes for neuronal calcium channels. Neuropharmacology 32: 1151-9. 

Salzet M., Bulet P., Van Dorsselaer A and Malecha J (1993) Isolation, structural characterization and biological function of a lysine-conopressin in the central nervous system of the pharyngobdellid leech Erpobdella octoculata. Eur J Biochem 217: 897-903. 

Myers, R.A., Cruz, L.J., Rivier, J.E. and Olivera, B.M. (1993) Conus peptides as chemical probes for receptors and ion channels. Chem. Rev. 93: 1923-1936. [Review]

Ramilo CA., Zafaralla GC., Nadasdi L., Hammerland LG., Yoshikami, D., Gray WR., Kristipati R., Ramachandran J., Miljanich G., Olivera BM and Cruz, LJ (1992) Novel alpha- and omega-conotoxins from Conus striatus venom. Biochemistry 31: 9919-9926. 

Hammerland LG, Olivera BM, and Yoshikami D. (1992) Conantokin-G selectively inhibits N-methyl-D-aspartate-induced currents in Xenopus oocytes injected with mouse brain mRNA. Eur J Pharmacol. 226: 239-244
Description: NMDA antagonist. This novel toxin was isolated from the venom of the fish-hunting cone snail Conus geographus. It is also called "sleeper peptide", which is an antagonist of brain NMDA receptors. This antagonism has been attributed to a potent non-competitive inhibition of polyamine responses at the NMDA receptor complex Source.

Santos AD., Imperial JS., Chaudhary T., Beavis RC., Chait BT., Hunsperger JP., Olivera BM., Adams ME. and Hillyard DR (1992) Heterodimeric structure of the spider toxin omega-agatoxin IA revealed by precursor analysis and mass spectrometry. J Biol Chem 267: 20701-5. 

Hillyard DR, Monje VD, Mintz IM, Bean BP, Nadasdi L, Ramachandran J, Miljanich G, Azimi-Zoonooz A, McIntosh JM, Cruz, LJ, Imperial JS, Olivera BM (1992) A new Conus peptide ligand for mammalian presynaptic Ca2+ channels. Neuron 9:69-77

Olivera BM., Imperial JS., Cruz LJ., Bindokas VP., Venema VJ and Adams ME (1991) Calcium channel-targeted polypeptide toxins. Ann N Y Acad Sci 635: 114-22. 

Olivera BM., Rivier J., Scott JK., Hillyard DR and Cruz LJ (1991) Conotoxins. J Biol Chem 266: 22067-70.

Myers RA., Zafaralla GC., Gray WR., Abbott J., Cruz LJ and Olivera BM (1991) alpha-Conotoxins, small peptide probes of nicotinic acetylcholine receptors. Biochemistry 30: 9370-9377. 

Lev-Ram, V., Olivera, B.M., Levitan, I.B., Corpuz, G.P., Ramilo, C.A., Hillyard, D.R. and Cruz, L.J. (1991) Molluscan Conus venoms: A source of toxin probes for molluscan neuroboiology. In: Molluscan Neurobiology. Edited by K.S. Kits, H.H. Boer and J. Joose.  Proceedings of the 3rd Symposium on Molluscan Neurobiology, Amsterdam, the Netherlands, Aug 20-24 1990, North-Holland, Amsterdam / Oxford / New York, 1991 [Abstract: The approximately 50 different species of molluscivorous Conus marine snails use their venoms to prey on other molluscs. Although the physiological characterization of these venoms has just been initiated, extensive biochemical work has revealed that the venoms are very complex, with many disulfide rich peptides present in a single venom. Preliminary evidence that these components are likely to affect receptors and ion channels in  molluscan neurons is described here. The molluscivorous Conus are therefore a potentially rich source of specifically targeted ligands for the receptors and ion channels that are responsible for  molluscan nervous system function. We anticipate that these will become standard tools in  molluscan neurobiology] 

Mena EE., Gullak MF., Pagnozzi MJ., Richter KE., Rivier J., Cruz LJ and Olivera BM (1990) Conantokin-G: a novel peptide antagonist to the N-methyl-D-aspartic acid. (NMDA) receptor. Neurosci Lett 118: 241-244. 

Olivera BM., Gray WR., Zeikus R., McIntosh JM., Varga J., Rivier J., de Santos V and Cruz LJ (1985) Peptide neurotoxins from fish-hunting cone snails. Science 230: 1338-43. 

Olivera BM., Cruz LJ., de Santos V., LeCheminant GW., Griffin D., Zeikus R., McIntosh JM., Galyean R., Varga J., Gray WR., and Rivier, J. (1987) Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using omega-conotoxin from Conus magus venom. Biochemistry 26: 2086-90. 

Biological Activity : Omega-CgTx MVII A and Omega-CgTx GVI A (from Conus geographus) are both neuronal Ca2+ channels blockers and appear to compete for the same sites in mammalian brain, but they seem to present some differences in their receptor binding characteristics; in particular the high affinity binding of Omega-CgTx MVII A has narrower specificity in amphibian brain. Molecular Weight : 2,639.2 Solubility in : well in water and saline Purity min. : typically 97 % (HPLC) Storage recommendations : Stable in freeze dried state. In solution, keep at -20C. Source

Olivera BM., Rivier J., Clark C., Ramilo CA., Corpuz GP., Abogadie FC., Mena EE., Woodward SR., Hillyard DR and Cruz LJ (1990) Diversity of Conus neuropeptides. Science 249: 257-63.

Haack JA., Rivier J., Parks TN., Mena EE., Cruz LJ and Olivera BM (1990) Conantokin-T. A gamma-carboxyglutamate containing peptide with N-methyl-d-aspartate antagonist activity. J Biol Chem 265: 6025-9. Source

Woodward SR., Cruz LJ., Olivera BM and Hillyard DR (1990) Constant and hypervariable regions in conotoxin propeptides. EMBO J 9: 1015-20. 

Yoshikami, D., Bagabaldo Z and Olivera BM (1989) The inhibitory effects of omega-conotoxins on Ca channels and synapses. Ann N Y Acad Sci 560: 230-48. 

Hillyard DR., Olivera BM., Woodward S., Corpuz GP., Gray WR., Ramilo CA and Cruz LJ (1989) A molluscivorous Conus toxin: conserved frameworks in conotoxins. Biochemistry 28: 358-61. 

Zafaralla GC., Ramilo C., Gray WR., Karlstrom R., Olivera BM and Cruz LJ (1988) Phylogenetic specificity of cholinergic ligands: alpha-conotoxin SI. Biochemistry 27: 7102-7105. 

Gray, WR., Olivera, BM and Cruz, LJ (1988) Peptide toxins from venomous Conus snails. Ann. Rev. Biochem. 57: 665 -

Rivier J., Galyean R., Simon L., Cruz LJ., Olivera BM and Gray WR (1987) Total synthesis and further characterization of the gamma-carboxyglutamate-containing "sleeper" peptide from Conus geographus venom. Biochemistry 26: 8508-12. 

Cruz LJ., de Santos V., Zafaralla GC., Ramilo CA., Zeikus R., Gray WR and Olivera BM (1987) Invertebrate vasopressin/oxytocin homologs. Characterization of peptides from Conus geographus and Conus straitus venoms. J Biol Chem 262: 15821-4. 

EARLIER 1981-1986

Olivera BM., Gray WR., Zeikus R., McIntosh JM., Varga J., Rivier J., de Santos V and Cruz LJ (1985) Peptide neurotoxins from fish-hunting cone snails. Science 230: 1338-43. 

Cruz LJ., Gray WR., Olivera BM., Zeikus RD., Kerr L., Yoshikami, D. and Moczydlowski E (1985) Conus geographus toxins that discriminate between neuronal and muscle sodium channels. J Biol Chem 260: 9280-9288. 

McIntosh JM., Olivera BM., Cruz LJ and Gray WR (1984) Gamma-carboxyglutamate in a neuroactive toxin. J Biol Chem 259: 14343-6. 

Olivera BM., McIntosh JM., Cruz LJ., Luque FA and Gray WR (1984) Purification and sequence of a presynaptic peptide toxin from Conus geographus venom. Biochemistry 23: 5087-5090. 

Gray WR., Luque FA., Galyean R., Atherton E., Sheppard RC., Stone BL., Reyes A., Alford J., McIntosh M., Olivera BM., et al(1984) Conotoxin GI: disulfide bridges, synthesis, and preparation of iodinated derivatives. Biochemistry 23: 2796-802. 

Gray WR., Rivier JE., Galyean R., Cruz LJ and Olivera BM (1983) Conotoxin MI. Disulfide bonding and conformational states. J Biol Chem 258: 12247-51. 

McIntosh M., Cruz LJ., Hunkapiller MW., Gray WR and Olivera BM (1982) Isolation and structure of a peptide toxin from the marine snail Conus magus. Arch Biochem Biophys 218: 329-34. 

Gray WR., Luque A., Olivera BM., Barrett J and Cruz LJ (1981) Peptide toxins from Conus geographus venom. J Biol Chem 256: 4734-40. 

Cruz, L.Z., Gray, W.R. and Olivera, B.M. (1978) Purification and properties of a myotoxin from Conus geographus. Archs. Biochem. Biophys. 190: 539-548 

BGL December 2001


 
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