Kaliotoxin
The amino acid sequence of Kaliotoxin |
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N - Gly - Val - Glu - Ile - Asn - Val - Lys - Cys - Ser - Gly - Ser - Pro - Gln - Cys - Leu - Lys - Pro - Cys - Lys - Asp - Ala - Gly - Met - Arg - Phe - Gly - Lys - Cys - Met - Asn - Arg - Lys - Cys - His - Cys - Thr - Pro - Lys - OH |
Kaliotoxin (KTX) inhibits potassium flux through the Kv1.3 voltage-gated potassium channel and calcium-activated potassium channels by physically blocking the channel-entrance and inducing a conformational change in the K+-selectivity filter of the channel.
Sources
KTX is a
Chemistry
Kaliotoxin is a 4-kDa polypeptide chain, containing 38
Target
KTX binds to the Kv1.3 voltage-gated potassium channel and the Calcium-activated potassium channels (BK channels). (Lange A et al., Crest M et al., Zachariae U et al., Aiyar J et al.,) These channels control several regulating processes, including neurotransmitter release, heart rate, insulin secretion, smooth muscle contraction. (Wickenden A et al.) Kv1.3 channels also play a critical role in regulating the function of effector memory T cells, the subset implicated in many autoimmune disorders, and blockade of Kv1.3 channels by kaliotoxin ameliorates disease in rat models of multiple sclerosis and bone resorption due to periodontitis. (Beeton C et al., Valverde P et al., Cahalan and Chandy)
Mode of action
The toxin binds to the external vestibule of the channel, and a critical lysine residue (K27), protrudes into the pore and plugs it (Aiyar J et al., 1995, 1996). The positively charged amino-group of the K27 chain fits into the selectivity filter near the G77 chain (
References
1. Korukottu J et al., High-resolution 3D structure determination of kaliotoxin by solid-state NMR spectroscopy. PLoS ONE. 2008 Jun 4;3(6):e2359
2. Zachariae U et al., The molecular mechanism of toxin-induced conformational changes in a potassium channel: relation to C-type inactivation. Structure. 2008 May;16(5):747-54
3. Catterall WA et al., Voltage-gated ion channels and gating modifier toxins. Toxicon. 2007 Feb;49(2):124-41
4. Lange A et al., Toxin-induced conformational changes in a potassium channel revealed by solid-state NMR. Nature. 2006 Apr 13;440(7086):959-62
5. Kunqian Y et al., Computational simulations of interactions of scorpion toxins with the voltage-gated potassium ion channel. Biophys J. 2004 Jun;86(6):3542-55
6. Wickenden A et al., K(+) channels as therapeutic drug targets. Pharmacol Ther. 2002 Apr-May;94(1-2):157-82.
7. Crest M et al., Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca(2+)-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom. J Biol Chem. 1992 Jan 25;267(3):1640-7
8. Aiyar J et al., Topology of the pore-region of a K+ channel revealed by the NMR-derived structures of scorpion toxins. [Neuron 1995 15:1169-1181]
9. Aiyar J. et al., The signature sequence of voltage-gated potassium channels projects into the external vestibule.[J Biol Chem. 1996 Dec 6;271(49):31013-6]
10. Beeton C et al., Selective blocking of voltage-gated K+ channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation. [J Immunol. 2001 Jan 15;166(2):936-44]
11. Valverde P et al., Selective blockade of voltage-gated potassium channels reduces inflammatory bone resorption in experimental periodontal disease. [J Bone Miner Res. 2004 Jan;19(1):155-64.]
12. Cahalan MD and Chandy KG. The functional network of ion channels in T lymphocytes. [Immunol Rev. 2009 Sep;231(1):59-87.]
13. Doyle DA et al., The structure of the potassium channel: molecular basis of K+ conduction and selectivity. [Science. 1998 Apr 3;280(5360):69-77]
14. MacKinnon R et al., Structural conservation in prokaryotic and eukaryotic potassium channels. [Science. 1998 Apr 3;280(5360):106-9]