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==Solution structure of Crotamine, a neurotoxin from Crotalus durissus terrificus==
==Solution structure of Crotamine, a neurotoxin from Crotalus durissus terrificus==
<StructureSection load='1h5o' size='340' side='right'caption='[[1h5o]], [[NMR_Ensembles_of_Models | 26 NMR models]]' scene=''>
<StructureSection load='1h5o' size='340' side='right'caption='[[1h5o]]' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1h5o]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Crotalus_durissus_terrificus Crotalus durissus terrificus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H5O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1H5O FirstGlance]. <br>
<table><tr><td colspan='2'>[[1h5o]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Crotalus_durissus_terrificus Crotalus durissus terrificus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1H5O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1H5O FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1h5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h5o OCA], [https://pdbe.org/1h5o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h5o RCSB], [https://www.ebi.ac.uk/pdbsum/1h5o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h5o ProSAT]</span></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1h5o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1h5o OCA], [https://pdbe.org/1h5o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1h5o RCSB], [https://www.ebi.ac.uk/pdbsum/1h5o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1h5o ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/MYXC_CRODU MYXC_CRODU]] This toxin specifically modifies voltage-gated sodium channels (Nav), it exhibits analgesic activity and causes severe muscle necrosis by a non-enzymatic mechanism. Moreover, it actively interacts with lipid membranes.<ref>PMID:1176086</ref> <ref>PMID:9839677</ref>
[https://www.uniprot.org/uniprot/MYC2_CRODU MYC2_CRODU] Cationic peptide that possesses multiple functions. It acts as a cell-penetrating peptide (CPP), and as a potent voltage-gated potassium channel inhibitor. It exhibits antimicrobial activities, hind limb paralysis, and severe muscle necrosis by a non-enzymatic mechanism. As a cell-penetrating peptide, crotamine has high specificity for actively proliferating cells, and interacts inside the cell with subcellular and subnuclear structures, like vesicular compartments, chromosomes and centrioles. It penetrates into the cells as fast as five minutes after its addition to cell culture medium (PubMed:18662711). In vivo, after intraperitoneal administration, it is found in cells of peritoneal fluid and bone marrow, demonstrating preferential nuclear and perinuclear localization. To enter the cell, it interacts with the chains of heparan sulfate membrane proteoglycan (HSPG), and is endocytosed (in complex with HSPG) in vesicles which are transported into the cell with the help of clathrin. Inside the cell, crotamine accumulates in lysosomal vesicles. As soon as the peptide accumulates in endosomes/lysosomes vesicles, these compartments are disrupted and their contents released into the cytosol. This loss of lysosomal content induces cell death at high concentrations, or promotes the distribution of crotamine in cytoplasmic compartments, which is a step before crotamine nuclear uptake (PubMed:15231729, PubMed:17491023). As a potassium channel inhibitor, this toxin selectively inhibits Kv1.1/KCNA1, Kv1.2/KCNA2 and Kv1.3/KCNA3 channels with an IC(50) of 369, 386 and 287 nM, respectively (PubMed:22498659). The inhibition of Kv1.3/KCNA channels induced by this toxin occurs rapidly and is voltage-independent. The channel inhibition is reversible after washing, suggesting a pure and classical channel blockage effect, without effects in potassium channel kinetics (PubMed:22498659). As an antimicrobial peptide, crotamine shows antibacterial activity against E.coli and B.subtilis, and antifungal activity against Candida spp., Trichosporon spp. and C.neoformans. It kills bacteria through membrane permeabilization.<ref>PMID:1176086</ref> <ref>PMID:15231729</ref> <ref>PMID:17491023</ref> <ref>PMID:17588630</ref> <ref>PMID:18662711</ref> <ref>PMID:19706485</ref> <ref>PMID:21386851</ref> <ref>PMID:22142367</ref> <ref>PMID:22498659</ref> <ref>PMID:23022146</ref> <ref>PMID:667499</ref> <ref>PMID:9839677</ref>  
== Evolutionary Conservation ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1h5o ConSurf].
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1h5o ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Crotamine is a component of the venom of the snake Crotalus durissus terrificus and it belongs to the myotoxin protein family. It is a 42 amino acid toxin cross-linked by three disulfide bridges and characterized by a mild toxicity (LD50 = 820 micro g per 25 g body weight, i.p. injection) when compared to other members of the same family. Nonetheless, it possesses a wide spectrum of biological functions. In fact, besides being able to specifically modify voltage-sensitive Na+ channel, it has been suggested to exhibit analgesic activity and to be myonecrotic. Here we report its solution structure determined by proton NMR spectroscopy. The secondary structure comprises a short N-terminal alpha-helix and a small antiparallel triple-stranded beta-sheet arranged in an alphabeta1beta2beta3 topology never found among toxins active on ion channels. Interestingly, some scorpion toxins characterized by a biological activity on Na+ channels similar to the one reported for crotamine, exhibit an alpha/beta fold, though with a beta1alphabeta2beta3 topology. In addition, as the antibacterial beta-defensins, crotamine interacts with lipid membranes. A comparison of crotamine with human beta-defensins shows a similar fold and a comparable net positive potential surface. To the best of our knowledge, this is the first report on the structure of a toxin from snake venom active on Na+ channel.
Solution structure of crotamine, a Na+ channel affecting toxin from Crotalus durissus terrificus venom.,Nicastro G, Franzoni L, de Chiara C, Mancin AC, Giglio JR, Spisni A Eur J Biochem. 2003 May;270(9):1969-79. PMID:12709056<ref>PMID:12709056</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1h5o" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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[[Category: Crotalus durissus terrificus]]
[[Category: Crotalus durissus terrificus]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Chiara, C De]]
[[Category: De Chiara C]]
[[Category: Franzoni, L]]
[[Category: Franzoni L]]
[[Category: Giglio, J R]]
[[Category: Giglio JR]]
[[Category: Mancin, C A]]
[[Category: Mancin CA]]
[[Category: Nicastro, G]]
[[Category: Nicastro G]]
[[Category: Spisni, A]]
[[Category: Spisni A]]
[[Category: Sodium channel affecting toxin]]
[[Category: Toxin]]
[[Category: Venom]]

Revision as of 14:28, 27 March 2024

Solution structure of Crotamine, a neurotoxin from Crotalus durissus terrificusSolution structure of Crotamine, a neurotoxin from Crotalus durissus terrificus

Structural highlights

1h5o is a 1 chain structure with sequence from Crotalus durissus terrificus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MYC2_CRODU Cationic peptide that possesses multiple functions. It acts as a cell-penetrating peptide (CPP), and as a potent voltage-gated potassium channel inhibitor. It exhibits antimicrobial activities, hind limb paralysis, and severe muscle necrosis by a non-enzymatic mechanism. As a cell-penetrating peptide, crotamine has high specificity for actively proliferating cells, and interacts inside the cell with subcellular and subnuclear structures, like vesicular compartments, chromosomes and centrioles. It penetrates into the cells as fast as five minutes after its addition to cell culture medium (PubMed:18662711). In vivo, after intraperitoneal administration, it is found in cells of peritoneal fluid and bone marrow, demonstrating preferential nuclear and perinuclear localization. To enter the cell, it interacts with the chains of heparan sulfate membrane proteoglycan (HSPG), and is endocytosed (in complex with HSPG) in vesicles which are transported into the cell with the help of clathrin. Inside the cell, crotamine accumulates in lysosomal vesicles. As soon as the peptide accumulates in endosomes/lysosomes vesicles, these compartments are disrupted and their contents released into the cytosol. This loss of lysosomal content induces cell death at high concentrations, or promotes the distribution of crotamine in cytoplasmic compartments, which is a step before crotamine nuclear uptake (PubMed:15231729, PubMed:17491023). As a potassium channel inhibitor, this toxin selectively inhibits Kv1.1/KCNA1, Kv1.2/KCNA2 and Kv1.3/KCNA3 channels with an IC(50) of 369, 386 and 287 nM, respectively (PubMed:22498659). The inhibition of Kv1.3/KCNA channels induced by this toxin occurs rapidly and is voltage-independent. The channel inhibition is reversible after washing, suggesting a pure and classical channel blockage effect, without effects in potassium channel kinetics (PubMed:22498659). As an antimicrobial peptide, crotamine shows antibacterial activity against E.coli and B.subtilis, and antifungal activity against Candida spp., Trichosporon spp. and C.neoformans. It kills bacteria through membrane permeabilization.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

References

  1. ↑ Laure CJ. [The primary structure of crotamine (author's transl)]. Hoppe Seylers Z Physiol Chem. 1975 Feb;356(2):213-5. PMID:1176086
  2. ↑ Kerkis A, Kerkis I, Radis-Baptista G, Oliveira EB, Vianna-Morgante AM, Pereira LV, Yamane T. Crotamine is a novel cell-penetrating protein from the venom of rattlesnake Crotalus durissus terrificus. FASEB J. 2004 Sep;18(12):1407-9. doi: 10.1096/fj.03-1459fje. Epub 2004 Jul 1. PMID:15231729 doi:http://dx.doi.org/10.1096/fj.03-1459fje
  3. ↑ Nascimento FD, Hayashi MA, Kerkis A, Oliveira V, Oliveira EB, Radis-Baptista G, Nader HB, Yamane T, Tersariol IL, Kerkis I. Crotamine mediates gene delivery into cells through the binding to heparan sulfate proteoglycans. J Biol Chem. 2007 Jul 20;282(29):21349-60. doi: 10.1074/jbc.M604876200. Epub 2007, May 9. PMID:17491023 doi:http://dx.doi.org/10.1074/jbc.M604876200
  4. ↑ Rizzi CT, Carvalho-de-Souza JL, Schiavon E, Cassola AC, Wanke E, Troncone LR. Crotamine inhibits preferentially fast-twitching muscles but is inactive on sodium channels. Toxicon. 2007 Sep 15;50(4):553-62. doi: 10.1016/j.toxicon.2007.04.026. Epub 2007 , May 18. PMID:17588630 doi:http://dx.doi.org/10.1016/j.toxicon.2007.04.026
  5. ↑ Hayashi MA, Nascimento FD, Kerkis A, Oliveira V, Oliveira EB, Pereira A, Radis-Baptista G, Nader HB, Yamane T, Kerkis I, Tersariol IL. Cytotoxic effects of crotamine are mediated through lysosomal membrane permeabilization. Toxicon. 2008 Sep 1;52(3):508-17. doi: 10.1016/j.toxicon.2008.06.029. Epub 2008, Jul 10. PMID:18662711 doi:http://dx.doi.org/10.1016/j.toxicon.2008.06.029
  6. ↑ Yount NY, Kupferwasser D, Spisni A, Dutz SM, Ramjan ZH, Sharma S, Waring AJ, Yeaman MR. Selective reciprocity in antimicrobial activity versus cytotoxicity of hBD-2 and crotamine. Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14972-7. doi:, 10.1073/pnas.0904465106. Epub 2009 Aug 13. PMID:19706485 doi:http://dx.doi.org/10.1073/pnas.0904465106
  7. ↑ Oguiura N, Boni-Mitake M, Affonso R, Zhang G. In vitro antibacterial and hemolytic activities of crotamine, a small basic myotoxin from rattlesnake Crotalus durissus. J Antibiot (Tokyo). 2011 Apr;64(4):327-31. doi: 10.1038/ja.2011.10. Epub 2011 Mar, 9. PMID:21386851 doi:http://dx.doi.org/10.1038/ja.2011.10
  8. ↑ Nascimento FD, Sancey L, Pereira A, Rome C, Oliveira V, Oliveira EB, Nader HB, Yamane T, Kerkis I, Tersariol IL, Coll JL, Hayashi MA. The natural cell-penetrating peptide crotamine targets tumor tissue in vivo and triggers a lethal calcium-dependent pathway in cultured cells. Mol Pharm. 2012 Feb 6;9(2):211-21. doi: 10.1021/mp2000605. Epub 2011 Dec 23. PMID:22142367 doi:http://dx.doi.org/10.1021/mp2000605
  9. ↑ Peigneur S, Orts DJ, Prieto da Silva AR, Oguiura N, Boni-Mitake M, de Oliveira EB, Zaharenko AJ, de Freitas JC, Tytgat J. Crotamine pharmacology revisited: novel insights based on the inhibition of KV channels. Mol Pharmacol. 2012 Jul;82(1):90-6. doi: 10.1124/mol.112.078188. Epub 2012 Apr, 12. PMID:22498659 doi:http://dx.doi.org/10.1124/mol.112.078188
  10. ↑ Yamane ES, Bizerra FC, Oliveira EB, Moreira JT, Rajabi M, Nunes GL, de Souza AO, da Silva ID, Yamane T, Karpel RL, Silva PI Jr, Hayashi MA. Unraveling the antifungal activity of a South American rattlesnake toxin crotamine. Biochimie. 2013 Feb;95(2):231-40. doi: 10.1016/j.biochi.2012.09.019. Epub 2012, Sep 26. PMID:23022146 doi:http://dx.doi.org/10.1016/j.biochi.2012.09.019
  11. ↑ Chang CC, Tseng KH. Effect of crotamine, a toxin of South American rattlesnake venom, on the sodium channel of murine skeletal muscle. Br J Pharmacol. 1978 Jul;63(3):551-9. doi: 10.1111/j.1476-5381.1978.tb07811.x. PMID:667499 doi:http://dx.doi.org/10.1111/j.1476-5381.1978.tb07811.x
  12. ↑ Mancin AC, Soares AM, Andriao-Escarso SH, Faca VM, Greene LJ, Zuccolotto S, Pela IR, Giglio JR. The analgesic activity of crotamine, a neurotoxin from Crotalus durissus terrificus (South American rattlesnake) venom: a biochemical and pharmacological study. Toxicon. 1998 Dec;36(12):1927-37. PMID:9839677
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