Kurtoxin is a 63-amino acid polypeptide isolated in the venom from

Kurtoxin is a 63-amino acid polypeptide isolated in the venom from the South African scorpion settings. hairpin loop (Gly39-Leu42) also differs between kurtoxin as well as the scorpion α-poisons. The length from the loop in kurtoxin (four residues) is certainly shorter than in various other poisons (around seven residues). Furthermore whereas the loop is certainly disordered and U0126-EtOH mixed up in formation from the main hydrophobic patch in kurtoxin it protrudes in the CSαβ primary and transforms toward the C-terminal segments in the scorpion α-toxins (Physique ?(Physique5).5). Because the C-terminal segments are disordered in both kurtoxin and scorpion α-toxins it is hard to assess structural differences in that region. However site-directed mutagenesis studies and functional assays of scorpion α-toxins have shown that there is a functional site composed of the five-residue reverse turn (Asp8-Cys12) and the C-terminal segment and that the conserved hydrophobic surface may be involved in maintaining the stability of the protein and its biological activity.103?107 Taken together these findings indicate that this core region of kurtoxin (i.e. the CSαβ motif) is usually well-defined and superimposes well on those of the scorpion α-toxins but the Asp8-Ile15 Gly39-Leu42 and C-terminal segments of kurtoxin are structurally different from those of the scorpion α-toxins suggesting it is these regions that are responsible for the functional differences between kurtoxin and scorpion α-toxins. Comparison of the Surface Profiles of Kurtoxin and Scorpion α-Poisons Kurtoxin includes five negatively billed and 11 favorably billed residues in its amino acidity sequence (Body ?(Figure1) 1 and many of these charged residues except Asp8 are highly open in the water-accessible surface area from the molecule. The medial side string air of Asp8 in AaH II forms a hydrogen connection using the amide proton U0126-EtOH of Val10 and the medial side string of Gln8 in Lqh III forms a NOV hydrogen connection using the air of Val13.100 Asp8 of kurtoxin is directed toward Lys13 U0126-EtOH and Arg14 (Figure ?(Figure6A).6A). Although there are no experimental data for the hydrogen connection connections between Asp8 and every other residues in kurtoxin some aspect string oxygens of Asp8 in 20 ensemble buildings are close more than enough to create hydrogen bonds with Lys13 and/or Arg14 in the motivated kurtoxin buildings. Along the α-helix the negative and positive fees align toward the solvent-accessible area from the molecule in both scorpion α-poisons and kurtoxin (Body ?(Figure6) 6 suggesting that feature could be involved in ion channel binding and determining selectivity.100 Kurtoxin is highly basic as compared to the α-scorpion toxins; the net charge of kurtoxin is definitely +6 while the others have net charges ranging from ?2 to +3. As demonstrated in Figure ?Number1 1 the two hydrophobic residues (Val13 and Tyr14) conserved in all scorpion α-toxins except AaH II are replaced with two positively charged residues (Lys13 and Arg14 respectively) in kurtoxin. Number ?Figure6B6B demonstrates the side chains of Val13 and Tyr14 in Lqq III (an anti-insect α-toxin) are largely buried in the molecular core. By contrast Lys13 and Arg14 in kurtoxin are exposed to solvent (Number ?(Figure6A)6A) and form a local electropositive surface (Figure ?(Figure4D).4D). In addition a large electropositive patch (surface area of 660 ?2) is formed from the five positively charged C-terminal residues (Arg54 Lys56 Arg57 Arg60 and Arg62). This is U0126-EtOH in contrast to the C-terminal structure of Lqq III which consists of only two positively charged residues (Arg58 and Lys62). The water-exposed positively charged U0126-EtOH residues of kurtoxin form a distinctive large electropositive surface which is located round the five-residue reverse change and C-terminal section and is the proposed Na+ channel binding site in scorpion α-toxins.104 Figure 6 Ribbon diagrams and heavy atom side chains of kurtoxin (A) and Lqq III (B). The surface hydrophobic patches and charged residues are indicated: reddish for the negatively charged amino acids are coloured blue for the positively charged amino acids purple … A surface hydrophobic patch is definitely a conserved feature of all scorpion α-toxins and is involved in mediating their connection with Na+ channels.108 109 The orthogonal arrangement of the aromatic side chains in the surface hydrophobic patch termed a “herringbone” structure is found in all scorpion α-toxins and has been.