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A 3D structural model of RsXXVIA, an ω-conotoxin

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The pharmacological relevance of peptides isolated from cone snails is gaining interest, particularly for pain management. Conotoxins are small well-structured peptides with specific functions over a number of specific physiological targets. Despite the large number and variety of toxins that these organisms can produce, only a handful of three-dimensional structures has been experimentally determined. Theoretical models of toxins, developed with bioinformatics method, contribute to the understanding of the structure and function of these peptides. RsXXVIA is a conotoxin previously isolated from the Conus regularis venom that has been shown to block N-type calcium channels. In this work, we modeled 12 theoretical cysteine frameworks (disulfide bonds) to elucidate the 3D structure of RsXXIVA to explain its activity. We used, as a template, the ω-conotoxin MVIIA (ziconotide), a prototype conotoxin with high sequence similarity to RsXXVIA. Particularly, the spatial arrangement of two amino acid residues, Lys2 and Tyr13 (in ziconotide), responsible for the pharmacological activity was taken into account. Remarkably, 3D models rendered a particularly suitable spatial disposition of key amino acids responsible for the activity on the N-type calcium channel. Additionally, this work explains, through computational models, how the conotoxin might be acting on the channel, thus, paving the way to find the principal RsXXVIA’s physiological target.

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  1. 1.

    Olivera BM, Just Lecture EE (1996) Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology. Mol Biol Cell 8(1997):2101–2109

  2. 2.

    Bingham JP, Mitsunaga E, Bergeron ZL (2010) Drugs from slugs—past, present and future perspectives of omega-conotoxin research. Chem Biol Interact 183:1–18

  3. 3.

    Lewis RJ, Dutertre S, Vetter I, Christie MJ (2012) Conus venom peptide pharmacology. Pharmacol Rev 64:259–298

  4. 4.

    Norton RS, Olivera BM (2006) Conotoxins down under. Toxicon: official journal of the International Society on Toxinology 48:780–798

  5. 5.

    Puillandre N, Koua D, Favreau P, Olivera BM, Stocklin R (2012) Molecular phylogeny, classification and evolution of conopeptides. J Mol Evol 74:297–309

  6. 6.

    Dutertre S, Lewis RJ (2010) Use of venom peptides to probe ion channel structure and function. J Biol Chem 285:13315–13320

  7. 7.

    Mattei C, Legros C (2014) The voltage-gated sodium channel: a major target of marine neurotoxins. Toxicon: official journal of the International Society on Toxinology 91:84–95

  8. 8.

    McIntosh JM, Azam L, Staheli S, Dowell C, Lindstrom JM, Kuryatov A, Garrett JE, Marks MJ, Whiteaker P (2004) Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors. Mol Pharmacol 65:944–952

  9. 9.

    Wang CZ, Chi CW (2004) Conus peptides—a rich pharmaceutical treasure. Acta Biochim Biophys Sin 36:713–723

  10. 10.

    Buczek O, Bulaj G, Olivera BM (2005) Conotoxins and the posttranslational modification of secreted gene products. Cellular and molecular life sciences: CMLS 62:3067–3079

  11. 11.

    Garrett JE, Buczek O, Watkins M, Olivera BM, Bulaj G (2005) Biochemical and gene expression analyses of conotoxins in Conus textile venom ducts. Biochem Biophys Res Commun 328:362–367

  12. 12.

    Tayo LL, Lu B, Cruz LJ, Yates 3rd JR (2010) Proteomic analysis provides insights on venom processing in Conus textile. J Proteome Res 9:2292–2301

  13. 13.

    Lebbe EK, Peigneur S, Wijesekara I, Tytgat J (2014) Conotoxins targeting nicotinic acetylcholine receptors: an overview. Marine drugs 12:2970–3004

  14. 14.

    Olivera BM (2006) Conus peptides: biodiversity-based discovery and exogenomics. J Biol Chem 281:31173–31177

  15. 15.

    Woodward SR, Cruz LJ, Olivera BM, Hillyard DR (1990) Constant and hypervariable regions in conotoxin propeptides. EMBO J 9:1015–1020

  16. 16.

    Buczek O, Olivera BM, Bulaj G (2004) Propeptide does not act as an intramolecular chaperone but facilitates protein disulfide isomerase-assisted folding of a conotoxin precursor. Biochemistry 43:1093–1101

  17. 17.

    Kaas Q, Westermann JC, Craik DJ (2010) Conopeptide characterization and classifications: an analysis using ConoServer. Toxicon: official journal of the International Society on Toxinology 55:1491–1509

  18. 18.

    Craig AG, Bandyopadhyay P, Olivera BM (1999) Post-translationally modified neuropeptides from Conus venoms. European journal of biochemistry/FEBS 264:271–275

  19. 19.

    Prommer E (2006) Ziconotide: a new option for refractory pain. Drugs of today 42:369–378

  20. 20.

    Beal BR, Wallace MS (2016) An overview of pharmacologic management of chronic pain. Med Clin North Am 100:65–79

  21. 21.

    Bernaldez J, Roman-Gonzalez SA, Martinez O, Jimenez S, Vivas O, Arenas I, Corzo G, Arreguin R, Garcia DE, Possani LD, Licea A (2013) A Conus regularis conotoxin with a novel eight-cysteine framework inhibits CaV2.2 channels and displays an anti-nociceptive activity. Marine drugs 11:1188–1202

  22. 22.

    Luo S, Christensen S, Zhangsun D, Wu Y, Hu Y, Zhu X, Chhabra S, Norton RS, McIntosh JM (2013) A novel inhibitor of alpha9alpha10 nicotinic acetylcholine receptors from Conus vexillum delineates a new conotoxin superfamily. PLoS One 8:e54648

  23. 23.

    Zhang Y, Chen HS, Liu BX, Zhang CR, Li XF, Wang YC (2010) Melting of (MgO)(n) (n=18, 21, and 24) clusters simulated by molecular dynamics. J Chem Phys 132:194304

  24. 24.

    Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38 27-38

  25. 25.

    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612

  26. 26.

    Lee S (2013) Pharmacological inhibition of voltage-gated Ca(2+) channels for chronic pain relief. Curr Neuropharmacol 11:606–620

  27. 27.

    Kaas Q, Westermann JC, Halai R, Wang CKL, Craik DJ (2008) ConoServer, a database for conopeptide sequences and structures. Bioinformatics 24:445–446

  28. 28.

    Daly NL, Craik DJ (2009) Structural studies of conotoxins. IUBMB life 61:144–150

  29. 29.

    Dutton JL, Bansal PS, Hogg RC, Adams DJ, Alewood PF, Craik DJ (2002) A new level of conotoxin diversity, a non-native disulfide bond connectivity in alpha-conotoxin AuIB reduces structural definition but increases biological activity. J Biol Chem 277:48849–48857

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This work was possible thanks to the support of the Posgrado en Ciencias Biológicas de la Universidad Nacional Autónoma de México. This paper fulfills the requirement for the principal author to obtain the PhD degree in the Posgrado en Ciencias Biológicas de la UNAM. This work was supported by a grant from the Consejo Nacional de Ciencia y Tecnología (CONACyT-Mexico) with the number 189808.

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Correspondence to Roberto Arreguín-Espinosa.

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Román-González, S.A., Robles-Gómez, E.E., Reyes, J. et al. A 3D structural model of RsXXVIA, an ω-conotoxin. Struct Chem 28, 901–909 (2017). https://doi.org/10.1007/s11224-016-0877-8

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  • Conotoxin
  • Ion channels
  • Cone snail
  • Peptide
  • Pharmacology