View source for Conotoxin

{{Short description|Group of neurotoxins}}
{{missing information|genetic and architectural classification (ConoServer and PMC4278219)|date=April 2019}}
{{Infobox protein family
| Symbol = Toxin_8
| Name = Alpha conotoxin precursor
| image = alpha-Conotoxin from Conus pennaceus 1AKG.png
| width = 
| caption = 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}}.
| Pfam= PF07365
| InterPro= IPR009958
| SMART=
| PROSITE = PDOC60004
| SCOP = 1mii
| TCDB =
| OPM family = 148
| OPM protein = 1akg
| PDB =
}}
{{Infobox protein family
| Symbol =  Conotoxin
| Name = Omega conotoxin
| image =Ziconotide 1DW5.png
| width =
| caption =Schematic diagram of the three-dimensional [[protein structure|structure]] of ω-conotoxin MVIIA ([[ziconotide]]). [[Disulfide bond]]s are shown in gold. From {{PDB|1DW5}}.
| Pfam= PF02950
| InterPro= IPR004214
| SMART=
| PROSITE =
| SCOP = 2cco
| TCDB =
| OPM family= 112
| OPM protein= 1fyg
| PDB=
}}
A '''conotoxin''' is one of a group of [[Neurotoxicity|neurotoxic]] [[peptide]]s 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 bond]]s.  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 channel]]s.<ref name="pmid14715910">{{cite journal | vauthors = Terlau H, Olivera BM | title = Conus venoms: a rich source of novel ion channel-targeted peptides | journal = Physiol. Rev. | volume = 84 | issue = 1 | pages = 41–68 | year = 2004 | pmid = 14715910 | doi = 10.1152/physrev.00020.2003 }}</ref>
Over the last few decades conotoxins have been the subject of pharmacological interest.<ref name="pmid17932414">{{cite journal| vauthors=Olivera BM, Teichert RW| title=Diversity of the neurotoxic Conus peptides: a model for concerted pharmacological discovery. | journal=Molecular Interventions | year= 2007 | volume= 7 | issue= 5 | pages= 251–60 | pmid=17932414 | doi=10.1124/mi.7.5.7 | url=https://pubmed.ncbi.nlm.nih.gov/17932414  }}</ref>

The [[Median lethal dose|LD<sub>50</sub>]] of conotoxin ranges from 5-25&nbsp;μg/kg.<ref>{{cite web |url=http://www.aristatek.com/Newsletter/MAY08/TechSpeak.pdf |title=Archived copy |access-date=2017-03-31 |url-status=live |archive-url=https://web.archive.org/web/20170829050422/http://www.aristatek.com/Newsletter/MAY08/TechSpeak.pdf |archive-date=2017-08-29 }}</ref><ref>{{cite web |title=Biological Agent Reference Sheet - Conotoxin |url=https://www.ehso.emory.edu/content-guidelines/BARS_Conotoxin.pdf |publisher=Emory University}}</ref><ref>{{cite web |last1=Baker |first1=A.L. |url=http://cfb.unh.edu/phycokey/Choices/Toxins/Toxin%20ld50s/toxin%20ld50%20list.htm |website=PhycoKey |title=toxin ld50 list}}</ref>

==Hypervariability==
Conotoxins are hypervariable even within the same species. They do not act within a body where they are produced ([[endogenous]]ly) but act on other organisms.<ref name="pmid22954218">{{cite journal | vauthors = Olivera BM, Watkins M, Bandyopadhyay P, Imperial JS, de la Cotera EP, Aguilar MB, Vera EL, Concepcion GP, Lluisma A | title = Adaptive radiation of venomous marine snail lineages and the accelerated evolution of venom peptide genes | journal = Ann. N. Y. Acad. Sci. | volume = 1267 | issue = 1| pages = 61–70 |date=September 2012 | pmid = 22954218 | pmc = 3488454 | doi = 10.1111/j.1749-6632.2012.06603.x | bibcode = 2012NYASA1267...61O }}</ref> 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.<ref name="pmid22285376">{{cite journal | vauthors = Wong ES, Belov K | title = Venom evolution through gene duplications | journal = Gene | volume = 496 | issue = 1 | pages = 1–7 |date=March 2012 | pmid = 22285376 | doi = 10.1016/j.gene.2012.01.009 }}</ref> Variability in conotoxin components reduces the likelihood that prey organisms will develop resistance; thus [[cone snail]]s are under constant selective pressure to maintain [[Polymorphism (biology)|polymorphism]] in these genes because failing to evolve and adapt will lead to extinction (''[[Red Queen hypothesis]]'').<ref name="pmid21511358">{{cite journal | vauthors = Liow LH, Van Valen L, Stenseth NC | title = Red Queen: from populations to taxa and communities | journal = Trends Ecol. Evol. | volume = 26 | issue = 7 | pages = 349–58 |date=July 2011 | pmid = 21511358 | doi = 10.1016/j.tree.2011.03.016 | bibcode = 2011TEcoE..26..349L }}</ref>

==Disulfide connectivities==
Types of conotoxins also differ in the number and pattern of disulfide bonds.<ref name="PUB00016617">{{cite journal |vauthors=Jones RM, McIntosh JM |title=Cone venom--from accidental stings to deliberate injection |journal=Toxicon |volume=39 |issue=10 |pages=1447–1451 |year=2001 |pmid=11478951 |doi=10.1016/S0041-0101(01)00145-3|bibcode=2001Txcn...39.1447M }}</ref> The disulfide bonding network, as well as specific amino acids in inter-cysteine loops, provide the specificity of conotoxins.<ref name="PUB00016622">{{cite journal |vauthors=Sato K, Kini RM, Gopalakrishnakone P, Balaji RA, Ohtake A, Seow KT, Bay BH |title=lambda-conotoxins, a new family of conotoxins with unique disulfide pattern and protein folding. Isolation and characterization from the venom of Conus marmoreus |journal=J. Biol. Chem. |volume=275 |issue=50 |pages=39516–39522 |year=2000 |pmid=10988292 |doi=10.1074/jbc.M006354200|doi-access=free }}</ref>

==Types and biological activities==
As of 2005, five biologically active conotoxins have been identified. Each of the five conotoxins attacks a different target:

* α-conotoxin inhibits [[nicotinic acetylcholine receptor]]s at [[nerve]]s and [[muscle]]s.<ref name="pmid15182346">{{cite journal | vauthors = Nicke A, Wonnacott S, Lewis RJ | title = Alpha-conotoxins as tools for the elucidation of structure and function of neuronal nicotinic acetylcholine receptor subtypes | journal = Eur. J. Biochem. | volume = 271 | issue = 12 | pages = 2305–2319 | year = 2004 | pmid = 15182346 | doi = 10.1111/j.1432-1033.2004.04145.x | doi-access = free }}</ref>
* δ-conotoxin inhibits fast inactivation of [[voltage-dependent sodium channels]].<ref name="pmid15990094">{{cite journal | vauthors = Leipold E, Hansel A, Olivera BM, Terlau H, Heinemann SH | title = Molecular interaction of delta-conotoxins with voltage-gated sodium channels | journal = FEBS Lett. | volume = 579 | issue = 18 | pages = 3881–3884 | year = 2005 | pmid = 15990094 | doi = 10.1016/j.febslet.2005.05.077 | doi-access = free | bibcode = 2005FEBSL.579.3881L }}</ref>
* κ-conotoxin inhibits [[potassium channel]]s.<ref name="pmid9417043">{{cite journal | vauthors = Shon KJ, Stocker M, Terlau H, Stühmer W, Jacobsen R, Walker C, Grilley M, Watkins M, Hillyard DR, Gray WR, Olivera BM | title = kappa-Conotoxin PVIIA is a peptide inhibiting the shaker K+ channel | journal = J. Biol. Chem. | volume = 273 | issue = 1 | pages = 33–38 | year = 1998 | pmid = 9417043 | doi = 10.1074/jbc.273.1.33 | doi-access = free }}</ref>
* μ-conotoxin inhibits voltage-dependent [[sodium channel]]s in muscles.<ref name="pmid15246758">{{cite journal | vauthors = Li RA, Tomaselli GF | title = Using the deadly mu-conotoxins as probes of voltage-gated sodium channels | journal = Toxicon | volume = 44 | issue = 2 | pages = 117–122 | year = 2004 | pmid = 15246758 | doi = 10.1016/j.toxicon.2004.03.028 | pmc = 2698010 | bibcode = 2004Txcn...44..117L }}</ref>
* ω-conotoxin inhibits N-type [[voltage-dependent calcium channel]]s.<ref name="pmid10822250">{{cite journal | vauthors = Nielsen KJ, Schroeder T, Lewis R | title = Structure-activity relationships of omega-conotoxins at N-type voltage-sensitive calcium channels | journal = J. Mol. Recognit. | volume = 13 | issue = 2 | pages = 55–70 | year = 2000 | pmid = 10822250 | doi = 10.1002/(SICI)1099-1352(200003/04)13:2<55::AID-JMR488>3.0.CO;2-O| url = http://www3.interscience.wiley.com/cgi-bin/abstract/72502378/ABSTRACT | archive-url = https://archive.today/20110813050839/http://www3.interscience.wiley.com/cgi-bin/abstract/72502378/ABSTRACT | url-status = dead | archive-date = 2011-08-13 | format = abstract| url-access = subscription }}</ref> 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]].<ref name="pmid9792182">{{cite journal | vauthors = Bowersox SS, Luther R | title = Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus | journal = Toxicon | volume = 36 | issue = 11 | pages = 1651–1658 | year = 1998 | pmid = 9792182 | doi = 10.1016/S0041-0101(98)00158-5 | bibcode = 1998Txcn...36.1651B }}</ref>  Therefore, a synthetic version of ω-conotoxin M VII A has found application as an analgesic drug [[ziconotide]] (Prialt).<ref name="pmid16845440">{{cite journal | author = Prommer E | title = Ziconotide: a new option for refractory pain | journal = Drugs Today | volume = 42 | issue = 6 | pages = 369–78 | year = 2006 | pmid = 16845440 | doi = 10.1358/dot.2006.42.6.973534 }}</ref>

===Alpha===
Alpha conotoxins have two types of cysteine arrangements,<ref name="PUB00017022">{{cite journal |vauthors=Gray WR, Olivera BM, Zafaralla GC, Ramilo CA, Yoshikami D, Nadasdi L, Hammerland LG, Kristipati R, Ramachandran J, Miljanich G |year=1992 |title=Novel alpha- and omega-conotoxins from Conus striatus venom |journal=Biochemistry |volume=31 |issue=41 |pages=11864–11873 |doi=10.1021/bi00156a009 |pmid=1390774}}</ref> and are competitive nicotinic acetylcholine receptor antagonists.

===Delta, kappa, and omega ===
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.<ref name="PUB00016617" />

===Mu===
{{Infobox protein family
| Symbol = Mu-conotoxin
| Name = Mu-conotoxin
| image = PDB 1r9i EBI.jpg
| width = 
| caption = nmr solution structure of piiia toxin, nmr, 20 structures
| Pfam = PF05374
| Pfam_clan = CL0083 
| InterPro = IPR008036
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1gib
| TCDB = 
| OPM family = 112
| OPM protein = 1ag7
| CAZy = 
| CDD = 
}}
Mu-conotoxins have two types of cysteine arrangements, but the [[Trefoil knot fold|knottin scaffold]] is not observed.<ref name="pmid12006587">{{cite journal | vauthors = Nielsen KJ, Watson M, Adams DJ, Hammarström AK, Gage PW, Hill JM, Craik DJ, Thomas L, Adams D, Alewood PF, Lewis RJ | title= Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels| journal = J. Biol. Chem. | volume = 277 | issue = 30 | pages = 27247–55 |date=July 2002 | pmid = 12006587 | doi = 10.1074/jbc.M201611200 | url = https://researchonline.jcu.edu.au/266/1/thomas_1.pdf| doi-access = free }}</ref> Mu-conotoxins target the muscle-specific voltage-gated sodium channels,<ref name="PUB00016617" /> and are useful probes for investigating voltage-dependent sodium channels of excitable tissues.<ref name="pmid12006587"/><ref name="PUB00017021">{{cite journal |vauthors=Zeikus RD, Gray WR, Cruz LJ, Olivera BM, Kerr L, Moczydlowski E, Yoshikami D |title=Conus geographus toxins that discriminate between neuronal and muscle sodium channels |journal=J. Biol. Chem. |volume=260 |issue=16 |pages=9280–8 |year=1985 |doi=10.1016/S0021-9258(17)39364-X |pmid=2410412|doi-access=free }}</ref> Mu-conotoxins target the voltage-gated [[sodium]] channels, preferentially those of [[skeletal muscle]],<ref name="pmid11478951">{{cite journal | vauthors = McIntosh JM, Jones RM | title = Cone venom--from accidental stings to deliberate injection | journal = Toxicon | volume = 39 | issue = 10 | pages = 1447–51 |date=October 2001 | pmid = 11478951 | doi = 10.1016/S0041-0101(01)00145-3| bibcode = 2001Txcn...39.1447M }}</ref> and are useful probes for investigating [[voltage-dependent sodium channels]] of excitable [[tissue (biology)|tissue]]s.<ref name="pmid2410412">{{cite journal | vauthors = Cruz LJ, Gray WR, Olivera BM, Zeikus RD, Kerr L, Yoshikami D, Moczydlowski E | title = Conus geographus toxins that discriminate between neuronal and muscle sodium channels | journal = J. Biol. Chem. | volume = 260 | issue = 16 | pages = 9280–8 |date=August 1985 | doi = 10.1016/S0021-9258(17)39364-X | pmid = 2410412 | doi-access = free }}</ref>

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.<ref name="pmid12878039">{{cite journal| author=Floresca CZ| title=A comparison of the mu-conotoxins by [3H]saxitoxin binding assays in neuronal and skeletal muscle sodium channel. | journal=Toxicol Appl Pharmacol | year= 2003 | volume= 190 | issue= 2 | pages= 95–101 | pmid=12878039 | doi= 10.1016/s0041-008x(03)00153-4| url=https://pubmed.ncbi.nlm.nih.gov/12878039  }}</ref>

==See also==
* [[Conolidine]]
* [[Contryphan]], members of "conotoxin O2"
* [[Conantokins]], also known as "conotoxin B"

==References==
{{InterPro content|IPR004214|IPR008036}}
{{reflist|30em}}

==External links==
* {{MeshName|Conotoxins}}
* {{cite web|url=https://www.ibiology.org/archive/conus-peptides/|title=Conus Peptides|author=Baldomero "Toto" Olivera's Short Talk}}
* {{cite web | url = http://www.conoserver.org/ | title = ConoServer | vauthors = Kaas Q, Westermann JC, Halai R, Wang CK, Craik DJ | publisher =  Institute of Molecular Bioscience, The University of Queensland, Australia| quote = A database for conopeptide sequences and structures| access-date = 2009-06-02}}

{{Protein tertiary structure}}
{{Toxins}}
{{Ion channel modulators}}
{{Nicotinic acetylcholine receptor modulators}}

[[Category:Snail toxins]]
[[Category:Ion channel toxins]]
[[Category:Neurotoxins]]
[[Category:Nicotinic antagonists]]
[[Category:Peripheral membrane proteins]]