| Structural highlights
Function
KA121_TITSE Potently blocks Kv1.3/KCNA3, Kv1.2/KCNA2, and Shaker potassium channels (PubMed:24590385) and inhibits high conductance calcium-activated potassium channels (PubMed:10082164). The IC(50) of Kv1.3/KCNN3 and Kv1.2/KCNN2 are 0.55 nM and 6.19 nM respectively (PubMed:24590385). In addition, it stimulates the release of NO, IL-6 and TNF-alpha in J774.1 cells (PubMed:21549737) and presents a pro-inflammatory activity in mice (PubMed:23085190).[1] [2] [3] [4] KAX62_SCOPA Blocks voltage-gated potassium channels Kv1.2/KCNA2 (IC(50)=0.12-0.8 nM), KCa3.1/KCNN4 (IC(50)=1-2.2 nM), Shaker B (IC(50)=2.39-80 nM), Kv1.1/KCNA1 (IC(50)=37-45 or no activity, depending on the study), Kv1.3/KCNA3 (IC(50)=150-180 or no activity, depending on the study).[5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
Scorpion toxins interact with their target ion channels through multiple molecular contacts. Because a "gain of function" approach has never been described to evaluate the importance of the molecular contacts in defining toxin affinity, we experimentally examined whether increasing the molecular contacts between a toxin and an ion channel directly impacts toxin affinity. For this purpose, we focused on two scorpion peptides, the well-characterized maurotoxin with its variant Pi1-like disulfide bridging (MTX(Pi1)), used as a molecular template, and butantoxin (BuTX), used as an N-terminal domain provider. BuTX is found to be 60-fold less potent than MTX(Pi1) in blocking Kv1.2 (IC(50) values of 165 nM for BuTX versus 2.8 nM for MTX(Pi1)). Removal of its N-terminal domain (nine residues) further decreases BuTX affinity for Kv1.2 by 5.6-fold, which is in agreement with docking simulation data showing the importance of this domain in BuTX-Kv1.2 interaction. Transfer of the BuTX N-terminal domain to MTX(Pi1) results in a chimera with five disulfide bridges (BuTX-MTX(Pi1)) that exhibits 22-fold greater affinity for Kv1.2 than MTX(Pi1) itself, in spite of the lower affinity of BuTX as compared to MTX(Pi1). Docking experiments performed with the 3-D structure of BuTX-MTX(Pi1) in solution, as solved by (1)H-NMR, reveal that the N-terminal domain of BuTX participates in the increased affinity for Kv1.2 through additional molecular contacts. Altogether, the data indicate that acting on molecular contacts between a toxin and a channel is an efficient strategy to modulate toxin affinity.
Increasing the molecular contacts between maurotoxin and Kv1.2 channel augments ligand affinity.,M'Barek S, Chagot B, Andreotti N, Visan V, Mansuelle P, Grissmer S, Marrakchi M, El Ayeb M, Sampieri F, Darbon H, Fajloun Z, De Waard M, Sabatier JM Proteins. 2005 Aug 15;60(3):401-11. PMID:15971207[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Novello JC, Arantes EC, Varanda WA, Oliveira B, Giglio JR, Marangoni S. TsTX-IV, a short chain four-disulfide-bridged neurotoxin from Tityus serrulatus venom which acts on Ca2+-activated K+ channels. Toxicon. 1999 Apr;37(4):651-60. PMID:10082164
- ↑ Zoccal KF, Bitencourt Cda S, Secatto A, Sorgi CA, Bordon Kde C, Sampaio SV, Arantes EC, Faccioli LH. Tityus serrulatus venom and toxins Ts1, Ts2 and Ts6 induce macrophage activation and production of immune mediators. Toxicon. 2011 Jun;57(7-8):1101-8. doi: 10.1016/j.toxicon.2011.04.017. Epub 2011, Apr 29. PMID:21549737 doi:https://dx.doi.org/10.1016/j.toxicon.2011.04.017
- ↑ Zoccal KF, Bitencourt Cda S, Sorgi CA, Bordon Kde C, Sampaio SV, Arantes EC, Faccioli LH. Ts6 and Ts2 from Tityus serrulatus venom induce inflammation by mechanisms dependent on lipid mediators and cytokine production. Toxicon. 2013 Jan;61:1-10. doi: 10.1016/j.toxicon.2012.10.002. Epub 2012 Oct 22. PMID:23085190 doi:https://dx.doi.org/10.1016/j.toxicon.2012.10.002
- ↑ Cerni FA, Pucca MB, Peigneur S, Cremonez CM, Bordon KC, Tytgat J, Arantes EC. Electrophysiological characterization of Ts6 and Ts7, K(+) channel toxins isolated through an improved Tityus serrulatus venom purification procedure. Toxins (Basel). 2014 Feb 28;6(3):892-913. doi: 10.3390/toxins6030892. PMID:24590385 doi:https://dx.doi.org/10.3390/toxins6030892
- ↑ Carlier E, Avdonin V, Geib S, Fajloun Z, Kharrat R, Rochat H, Sabatier JM, Hoshi T, De Waard M. Effect of maurotoxin, a four disulfide-bridged toxin from the chactoid scorpion Scorpio maurus, on Shaker K+ channels. J Pept Res. 2000 Jun;55(6):419-27. PMID:10888198
- ↑ Avdonin V, Nolan B, Sabatier JM, De Waard M, Hoshi T. Mechanisms of maurotoxin action on Shaker potassium channels. Biophys J. 2000 Aug;79(2):776-87. PMID:10920011 doi:https://dx.doi.org/10.1016/S0006-3495(00)76335-1
- ↑ Castle NA, London DO, Creech C, Fajloun Z, Stocker JW, Sabatier JM. Maurotoxin: a potent inhibitor of intermediate conductance Ca2+-activated potassium channels. Mol Pharmacol. 2003 Feb;63(2):409-18. PMID:12527813
- ↑ Regaya I, Beeton C, Ferrat G, Andreotti N, Darbon H, De Waard M, Sabatier JM. Evidence for domain-specific recognition of SK and Kv channels by MTX and HsTx1 scorpion toxins. J Biol Chem. 2004 Dec 31;279(53):55690-6. Epub 2004 Oct 21. PMID:15498765 doi:M410055200
- ↑ Pimentel C, M'Barek S, Visan V, Grissmer S, Sampieri F, Sabatier JM, Darbon H, Fajloun Z. Chemical synthesis and 1H-NMR 3D structure determination of AgTx2-MTX chimera, a new potential blocker for Kv1.2 channel, derived from MTX and AgTx2 scorpion toxins. Protein Sci. 2008 Jan;17(1):107-18. Epub 2007 Nov 27. PMID:18042681 doi:ps.073122908
- ↑ Kharrat R, Mabrouk K, Crest M, Darbon H, Oughideni R, Martin-Eauclaire MF, Jacquet G, el Ayeb M, Van Rietschoten J, Rochat H, Sabatier JM. Chemical synthesis and characterization of maurotoxin, a short scorpion toxin with four disulfide bridges that acts on K+ channels. Eur J Biochem. 1996 Dec 15;242(3):491-8. PMID:9022673
- ↑ Kharrat R, Mansuelle P, Sampieri F, Crest M, Oughideni R, Van Rietschoten J, Martin-Eauclaire MF, Rochat H, El Ayeb M. Maurotoxin, a four disulfide bridge toxin from Scorpio maurus venom: purification, structure and action on potassium channels. FEBS Lett. 1997 Apr 14;406(3):284-90. PMID:9136903
- ↑ M'Barek S, Chagot B, Andreotti N, Visan V, Mansuelle P, Grissmer S, Marrakchi M, El Ayeb M, Sampieri F, Darbon H, Fajloun Z, De Waard M, Sabatier JM. Increasing the molecular contacts between maurotoxin and Kv1.2 channel augments ligand affinity. Proteins. 2005 Aug 15;60(3):401-11. PMID:15971207 doi:https://dx.doi.org/10.1002/prot.20509
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