Maurotoxin: Difference between revisions

Content deleted Content added

Inline

Latest revision as of 20:35, 23 June 2022

The protein NMR structure of maurotoxin, illustrating the fluctuations in the protein's native state in solution. The protein backbone is shown in red, the alpha carbons of the eight cysteine residues in green, and the disulfide bridges in yellow. Compare the disulfide bond connectivity to HsTx1 below.

The protein NMR structure of HsTx1, a scorpion toxin with a canonical disulfide bond connectivity.

Maurotoxin (abbreviated MTX) is a peptide toxin from the venom of the Tunisian chactoid scorpion Scorpio maurus palmatus, from which it was first isolated and from which the chemical gets its name. It acts by blocking several types of voltage-gated potassium channel.

Chemistry[edit]

Maurotoxin is a peptide of 34 amino acids (sequence VSCTGSKDCYAPCRKQTGCPNAKCINKSCKCYGC) cross-linked by four disulfide bridges (Cys3-Cys24, Cys9-Cys29, Cys13-Cys19, Cys31-Cys34), with an atypical pattern of organization compared with other scorpion toxins; this unusual pairing of cysteine residues may be mediated by the presence of adjacent prolines. The peptide contains an alpha helix linked by two disulfide bridges to a two-stranded antiparallel beta sheet.

Target[edit]

Scorpion toxins constitute the largest group of potassium (K⁺) channel blockers and are useful pharmacological probes to investigate ion channels and their functions.

Maurotoxin (MTX) blocks various K⁺ -channels:

Apamin-sensitive small conductance Ca²⁺ - activated K⁺ channels (SK)
Intermediate conductance Ca²⁺ - activated K⁺ channels (IK)
Several types of voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.3 and shaker B)

The structural and pharmacological features of MTX suggest that MTX belongs to a new class of natural K⁺ channel blockers structurally intermediate between the Na⁺ (60–70 residues and four disulfide bridges) and K⁺ channel scorpion toxin families (less than 40 residues and three disulfide bridges).

The intermediate conductance Ca²⁺-activated K⁺ (IK) channel is present in peripheral tissues, including secretory epithelia and blood cells. An important physiological role of the IK channel is to help maintain large electrical gradients for the sustained transport of ions such as Ca²⁺ that controls T lymphocyte (T cell) proliferation. Thus IK blockers could be potential immunosuppressants for the treatment of autoimmune disorders (such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis).

Mode of action[edit]

MTX occludes the pore region of various potassium channels (Kv1.2, IKCa1, Kv1.3) by establishing strong interactions between its lysine-23 residue and the glycine-tyrosine-glycine-aspartate (GYGD) motif of the channel. MTX thus blocks the channels by binding in the external vestibule of the pore to block the ion conduction pathway. Although Kv1.1, Kv1.2, and Kv1.3 have a very similar pore structure, they display different pharmacological sensitivity to MTX.

References[edit]

Carlier, E., et al., Effect of maurotoxin, a four disulfide-bridged toxin from the chactoid scorpion Scorpio maurus, on Shaker K+ channels. J Pept Res, 2000. 55(6): p. 419–27.
Castle, N.A., et al., Maurotoxin: a potent inhibitor of intermediate conductance Ca2+-activated potassium channels. Mol Pharmacol, 2003. 63(2): p. 409–18.
Fu, W., et al., Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels. Biophys J, 2002. 83(5): p. 2370–85.
Jensen, B.S., et al., The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression. Expert Opin Ther Targets, 2002. 6(6): p. 623–36.
Kharrat, R., et al., Chemical synthesis and characterization of maurotoxin, a short scorpion toxin with four disulfide bridges that acts on K+ channels. Eur J Biochem, 1996. 242(3): p. 491–8.
M'Barek, S., et al., A maurotoxin with constrained standard disulfide bridging: innovative strategy of chemical synthesis, pharmacology, and docking on K+ channels. J Biol Chem, 2003. 278(33): p. 31095–104.
Rochat, H., et al., Maurotoxin, a four disulfide bridges scorpion toxin acting on K+ channels. Toxicon, 1998. 36(11): p. 1609–11.
Visan, V., et al., Mapping of maurotoxin binding sites on hKv1.2, hKv1.3, and hIKCa1 channels. Mol Pharmacol, 2004. 66(5): p. 1103–12.

@@ Line 1: / Line 1: @@
+{{Short description|Toxin in scorpions}}
-{{cleanup-date|November 2006}}
+{{Inline citations|date=June 2019}}[[Image:Maurotoxin 1txm.png|thumb|right|250px|The [[protein NMR]] structure of maurotoxin, illustrating the fluctuations in the protein's [[native state]] in solution. The protein backbone is shown in red, the [[alpha carbon]]s of the eight [[cysteine]] residues in green, and the [[disulfide bridge]]s in yellow. Compare the disulfide bond connectivity to HsTx1 below.]]
-'''Maurotoxin''' is a toxin isolated from a scorpion, which blocks several potassium channels.
+[[Image:Hstx1_1quz.png|thumb|right|250px|The [[protein NMR]] structure of HsTx1, a scorpion toxin with a canonical disulfide bond connectivity.]]
-== Etymology and source ==
-The word Maurotoxin is retrieved from the initially isolated source, the Tunisian chactoid scorpion, ''scorpio maurus palmatus''. MTX is only 0.6% of the total proteins in a crude venom, which means it is not widely available. Chemical solid-phase synthesis has been used to study its structural as pharmacological characteristics.
+'''Maurotoxin''' (abbreviated MTX) is a [[peptide]] [[toxin]] from the venom of the Tunisian chactoid [[scorpion]] ''[[Scorpio maurus]] palmatus'', from which it was first isolated and from which the chemical gets its name. It acts by blocking several types of [[voltage-gated potassium channel]].
 == Chemistry ==
+Maurotoxin is a peptide of 34 [[amino acid]]s (sequence VSCTGSKDCYAPCRKQTGCPNAKCINKSCKCYGC) cross-linked by four [[disulfide bridge]]s (Cys3-Cys24, Cys9-Cys29, Cys13-Cys19, Cys31-Cys34), with an atypical pattern of organization compared with other scorpion toxins; this unusual pairing of [[cysteine]] residues may be mediated by the presence of adjacent [[proline]]s. The peptide contains an [[alpha helix]] linked by two disulfide bridges to a two-stranded antiparallel [[beta sheet]].
-Maurotoxin is a short-stain toxin, consisting of 34 residues and it belongs to a α-KTX toxin family. It is a basic, C-terminal animated, 34-mer peptide cross-linked by four disulfide bridges, with an atypical pattern of organization compared with conventional three-disulfide-bridged scorpion toxins. The α-helix of MTX is connected by two disulfide bridges to two different strands of the β-sheet instead of connecting the α-helix to the same strand.
 == Target ==
-Scorpion toxins constitute the largest group of potassium (K<sup>+</sup>) channel blockers and are useful pharmacological probes to investigate ion-specific channel proteins and their functions.
+Scorpion toxins constitute the largest group of [[potassium]] (K<sup>+</sup>) channel blockers and are useful pharmacological probes to investigate ion channels and their functions.
-Maurotoxin (MTX) acts on various K<sup>+</sup> -channels:
+Maurotoxin (MTX) blocks various K<sup>+</sup> -channels:
-* Apamin-sensitive small conductance Ca<sup>2+</sup> - activated K<sup>+</sup> channels (SK)
+* [[Apamin]]-sensitive small conductance [[calcium|Ca<sup>2+</sup>]] - activated [[potassium|K<sup>+</sup>]] channels (SK)
 * Intermediate conductance Ca<sup>2+</sup> - activated K<sup>+</sup> channels (IK)
-* Several types of voltage-gated Kv channels (Kv1.1, Kv1.2, Kv1.3 and shaker B)
+* Several types of [[voltage-gated potassium channel]]s (Kv1.1, Kv1.2, Kv1.3 and shaker B)
 The structural and pharmacological features of MTX suggest that MTX belongs to a new class of natural K<sup>+</sup> channel blockers structurally intermediate between the Na<sup>+</sup> (60–70 residues and four disulfide bridges) and K<sup>+</sup> channel scorpion toxin families (less than 40 residues and three disulfide bridges).
-The intermediate conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (IK) channel is like many K<sup>+</sup> channels, an assembly of four identical subunits each spanning the membrane six times and each contributing equally to the K<sup>+</sup> selectivity pore positioned centrally in the complex. Several toxins including maurotoxin potently block IK channels.
+The intermediate conductance Ca<sup>2+</sup>-activated K<sup>+</sup> (IK) channel is present in peripheral tissues, including secretory [[epithelia]] and [[blood cell]]s. An important physiological role of the IK channel is to help maintain large electrical gradients for the sustained transport of ions such as Ca<sup>2+</sup> that controls [[T lymphocyte]] (T cell) proliferation. Thus IK blockers could be potential [[immunosuppressant]]s for the treatment of autoimmune disorders (such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis).
-The IK channel is distributed in peripheral tissues, including secretory epithelia and blood cells. An important physiological role of the IK channel is to help maintain large electrical gradients for the sustained transport of ions such as Ca<sup>2+</sup> influx that controls T lymphocyte (T cell) proliferation. Hereby IK blockers could be potential immunosuppressants for the treatment of autoimmune disorders (such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis).
 == Mode of action ==
-MTX occludes the pore region of the channels (Kv1.2, IKCa1, Kv1.3) by establishing strong interactions between Lys23 and the GYGD motif.
+MTX occludes the pore region of various potassium channels (Kv1.2, IKCa1, Kv1.3) by establishing strong interactions between its [[lysine]]-23 residue and the [[glycine]]-[[tyrosine]]-[[glycine]]-[[aspartate]] (GYGD) motif of the channel. MTX thus blocks the channels by binding in the external vestibule of the pore to block the ion conduction pathway. Although Kv1.1, Kv1.2, and Kv1.3 have a very similar pore structure, they display different pharmacological sensitivity to MTX.
-MTX blocks the Kv1 channels by binding in the external vestibule of the pore to block the ion conduction pathway. Although Kv1.1, Kv1.2, and Kv1.3 have a very similar pore structure, they display different pharmacological activity inhibited by MTX. MTX can be used as a structural probe to identify the critical residues of the nonconserved poreforming sequence in the recognition of the Kv1 channels.
+== References ==
+# Carlier, E., ''et al.'', Effect of maurotoxin, a four disulfide-bridged toxin from the chactoid scorpion Scorpio maurus, on Shaker K+ channels. J Pept Res, 2000. 55(6): p. 419–27.
-== References ==
+# Castle, N.A., ''et al.'', Maurotoxin: a potent inhibitor of intermediate conductance Ca2+-activated potassium channels. Mol Pharmacol, 2003. 63(2): p. 409–18.
+# Fu, W., ''et al.'', Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels. Biophys J, 2002. 83(5): p. 2370–85.
+# Jensen, B.S., ''et al.'', The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression. Expert Opin Ther Targets, 2002. 6(6): p. 623–36.
+# Kharrat, R., ''et al.'', Chemical synthesis and characterization of maurotoxin, a short scorpion toxin with four disulfide bridges that acts on K+ channels. Eur J Biochem, 1996. 242(3): p. 491–8.
+# M'Barek, S., ''et al.'', A maurotoxin with constrained standard disulfide bridging: innovative strategy of chemical synthesis, pharmacology, and docking on K+ channels. J Biol Chem, 2003. 278(33): p. 31095–104.
+# Rochat, H., ''et al.'', Maurotoxin, a four disulfide bridges scorpion toxin acting on K+ channels. Toxicon, 1998. 36(11): p. 1609–11.
+# Visan, V., ''et al.'', Mapping of maurotoxin binding sites on hKv1.2, hKv1.3, and hIKCa1 channels. Mol Pharmacol, 2004. 66(5): p. 1103–12.
+{{Toxins}}
-# Carlier, E., et al., Effect of maurotoxin, a four disulfide-bridged toxin from the chactoid scorpion Scorpio maurus, on Shaker K+ channels. J Pept Res, 2000. 55(6): p. 419-27.
+{{Potassium channel blockers}}
-# Castle, N.A., et al., Maurotoxin: a potent inhibitor of intermediate conductance Ca2+-activated potassium channels. Mol Pharmacol, 2003. 63(2): p. 409-18.
+[[Category:Neurotoxins]]
-# Fu, W., et al., Brownian dynamics simulations of the recognition of the scorpion toxin maurotoxin with the voltage-gated potassium ion channels. Biophys J, 2002. 83(5): p. 2370-85.
+[[Category:Ion channel toxins]]
-# Jensen, B.S., et al., The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression. Expert Opin Ther Targets, 2002. 6(6): p. 623-36.
+[[Category:Scorpion toxins]]
-# Kharrat, R., et al., Chemical synthesis and characterization of maurotoxin, a short scorpion toxin with four disulfide bridges that acts on K+ channels. Eur J Biochem, 1996. 242(3): p. 491-8.
-# M'Barek, S., et al., A maurotoxin with constrained standard disulfide bridging: innovative strategy of chemical synthesis, pharmacology, and docking on K+ channels. J Biol Chem, 2003. 278(33): p. 31095-104.
-# Rochat, H., et al., Maurotoxin, a four disulfide bridges scorpion toxin acting on K+ channels. Toxicon, 1998. 36(11): p. 1609-11.
-# Visan, V., et al., Mapping of maurotoxin binding sites on hKv1.2, hKv1.3, and hIKCa1 channels. Mol Pharmacol, 2004. 66(5): p. 1103-12.