Theprotein NMR structure of maurotoxin, illustrating the fluctuations in the protein'snative state in solution. The protein backbone is shown in red, thealpha carbons of the eightcysteine residues in green, and thedisulfide bridges in yellow. Compare the disulfide bond connectivity to HsTx1 below.Theprotein NMR structure of HsTx1, a scorpion toxin with a canonical disulfide bond connectivity.
Maurotoxin (abbreviated MTX) is apeptidetoxin from the venom of the Tunisian chactoidscorpionScorpio maurus palmatus, from which it was first isolated and from which the chemical gets its name. It acts by blocking several types ofvoltage-gated potassium channel.
Maurotoxin is a peptide of 34amino acids (sequence VSCTGSKDCYAPCRKQTGCPNAKCINKSCKCYGC) cross-linked by fourdisulfide bridges (Cys3-Cys24, Cys9-Cys29, Cys13-Cys19, Cys31-Cys34), with an atypical pattern of organization compared with other scorpion toxins; this unusual pairing ofcysteine residues may be mediated by the presence of adjacentprolines. The peptide contains analpha helix linked by two disulfide bridges to a two-stranded antiparallelbeta sheet.
Scorpion toxins constitute the largest group ofpotassium (K+) channel blockers and are useful pharmacological probes to investigate ion channels and their functions.
Maurotoxin (MTX) blocks various K+ -channels:
Apamin-sensitive small conductanceCa2+ - activatedK+ channels (SK)
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 secretoryepithelia andblood 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 controlsT lymphocyte (T cell) proliferation. Thus IK blockers could be potentialimmunosuppressants for the treatment of autoimmune disorders (such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis).
MTX occludes the pore region of various potassium channels (Kv1.2, IKCa1, Kv1.3) by establishing strong interactions between itslysine-23 residue and theglycine-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.
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