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Zhu Ming-sheng - One of the best experts on this subject based on the ideXlab platform.

Jan Tytgat - One of the best experts on this subject based on the ideXlab platform.

  • active sites of spinoxin a potassium channel scorpion toxin elucidated by systematic alanine scanning
    Biochemistry, 2016
    Co-Authors: Steve Peigneur, Selvanayagam Nirthanan, Jan Tytgat, P Gopalakrishnakone, Yoko Yamaguchi, Chihiro Kawano, Takeru Nose, Kazuki Sato
    Abstract:

    Peptide toxins from scorpion venoms constitute the largest group of toxins that target the voltage-gated potassium channel (Kv). Spinoxin (SPX) isolated from the venom of scorpion Heterometrus spinifer is a 34-residue peptide neurotoxin cross-linked by four disulfide bridges. SPX is a potent inhibitor of Kv1.3 potassium channels (IC50 = 63 nM), which are considered to be valid molecular targets in the diagnostics and therapy of various autoimmune disorders and cancers. Here we synthesized 25 analogues of SPX and analyzed the role of each amino acid in SPX using alanine scanning to study its structure–function relationships. All synthetic analogues showed similar disulfide bond pairings and secondary structures as native SPX. Alanine replacements at Lys23, Asn26, and Lys30 resulted in loss of activity against Kv1.3 potassium channels, whereas replacements at Arg7, Met14, Lys27, and Tyr32 also largely reduced inhibitory activity. These results suggest that the side chains of these amino acids in SPX play an...

  • Assignment of voltage-gated potassium channel blocking activity to κ-ktx1.3, a non-toxic homologue of κ-hefutoxin-1, from Heterometrus spinifer venom
    Biochemical pharmacology, 2004
    Co-Authors: Selvanayagam Nirthanan, Joost Pil, Yousra Abdel-mottaleb, Yuko Sugahara, Ponnampalam Gopalakrishnakone, Jeremiah S. Joseph, Kazuki Sato, Jan Tytgat
    Abstract:

    Abstract A new family of weak K + channel toxins (designated κ-KTx) with a novel “bi-helical” scaffold has recently been characterized from Heterometrus fulvipes (Scorpionidae) venom. Based on the presence of the minimum functional dyad (Y5 and K19), κ-hefutoxin-1 (κ-KTx1.1) was investigated and found to block Kv 1.2 (IC 50 ∼40 μM) and Kv 1.3 (IC 50 ∼150 μM) channels. In the present study, κ-KTx1.3, that shares ∼60% identity with κ-hefutoxin 1, has been isolated from Heterometrus spinifer venom. Interestingly, despite the presence of the functional dyad (Y5 and K19), κ-KTx1.3 failed to reproduce the K + channel blocking activity of κ-hefutoxin-1. Since the dyad lysine in κ-KTx1.3 was flanked by another lysine (K20), it was hypothesized that this additional positive charge could hinder the critical electrostatic interactions known to occur between the dyad lysine and the Kv 1 channel selectivity filter. Hence, mutants of κ-KTx1.3, substituting K20 with a neutral (K20A) or a negatively (K20E) or another positively (K20R) charged amino acid were synthesized. κ-KTx1.3 K20E, in congruence with κ-hefutoxin 1 with respect to subtype selectivity and affinity, produced blockade of Kv 1.2 (IC 50  = 36.8 ± 4.9 μM) and Kv 1.3 (IC 50  = 53.7 ± 6.7 μM) but not Kv 1.1 channels. κ-KTx1.3 K20A produced blockade of both Kv 1.2 (IC 50  = 36.9 ± 4.9 μM) and Kv 1.3 (IC 50  = 115.7 ± 7.3 μM) and in addition, acquired affinity for Kv 1.1 channels (IC 50  = 110.7 ± 7.7 μM). κ-KTx1.3 K20R failed to produce any blockade on the channel subtypes tested. These data suggest that the presence of an additional charged residue in a position adjacent to the dyad lysine impedes the functional block of Kv 1 channels produced by κ-KTx1.3.

Kazuki Sato - One of the best experts on this subject based on the ideXlab platform.

  • active sites of spinoxin a potassium channel scorpion toxin elucidated by systematic alanine scanning
    Biochemistry, 2016
    Co-Authors: Steve Peigneur, Selvanayagam Nirthanan, Jan Tytgat, P Gopalakrishnakone, Yoko Yamaguchi, Chihiro Kawano, Takeru Nose, Kazuki Sato
    Abstract:

    Peptide toxins from scorpion venoms constitute the largest group of toxins that target the voltage-gated potassium channel (Kv). Spinoxin (SPX) isolated from the venom of scorpion Heterometrus spinifer is a 34-residue peptide neurotoxin cross-linked by four disulfide bridges. SPX is a potent inhibitor of Kv1.3 potassium channels (IC50 = 63 nM), which are considered to be valid molecular targets in the diagnostics and therapy of various autoimmune disorders and cancers. Here we synthesized 25 analogues of SPX and analyzed the role of each amino acid in SPX using alanine scanning to study its structure–function relationships. All synthetic analogues showed similar disulfide bond pairings and secondary structures as native SPX. Alanine replacements at Lys23, Asn26, and Lys30 resulted in loss of activity against Kv1.3 potassium channels, whereas replacements at Arg7, Met14, Lys27, and Tyr32 also largely reduced inhibitory activity. These results suggest that the side chains of these amino acids in SPX play an...

  • Assignment of voltage-gated potassium channel blocking activity to κ-ktx1.3, a non-toxic homologue of κ-hefutoxin-1, from Heterometrus spinifer venom
    Biochemical pharmacology, 2004
    Co-Authors: Selvanayagam Nirthanan, Joost Pil, Yousra Abdel-mottaleb, Yuko Sugahara, Ponnampalam Gopalakrishnakone, Jeremiah S. Joseph, Kazuki Sato, Jan Tytgat
    Abstract:

    Abstract A new family of weak K + channel toxins (designated κ-KTx) with a novel “bi-helical” scaffold has recently been characterized from Heterometrus fulvipes (Scorpionidae) venom. Based on the presence of the minimum functional dyad (Y5 and K19), κ-hefutoxin-1 (κ-KTx1.1) was investigated and found to block Kv 1.2 (IC 50 ∼40 μM) and Kv 1.3 (IC 50 ∼150 μM) channels. In the present study, κ-KTx1.3, that shares ∼60% identity with κ-hefutoxin 1, has been isolated from Heterometrus spinifer venom. Interestingly, despite the presence of the functional dyad (Y5 and K19), κ-KTx1.3 failed to reproduce the K + channel blocking activity of κ-hefutoxin-1. Since the dyad lysine in κ-KTx1.3 was flanked by another lysine (K20), it was hypothesized that this additional positive charge could hinder the critical electrostatic interactions known to occur between the dyad lysine and the Kv 1 channel selectivity filter. Hence, mutants of κ-KTx1.3, substituting K20 with a neutral (K20A) or a negatively (K20E) or another positively (K20R) charged amino acid were synthesized. κ-KTx1.3 K20E, in congruence with κ-hefutoxin 1 with respect to subtype selectivity and affinity, produced blockade of Kv 1.2 (IC 50  = 36.8 ± 4.9 μM) and Kv 1.3 (IC 50  = 53.7 ± 6.7 μM) but not Kv 1.1 channels. κ-KTx1.3 K20A produced blockade of both Kv 1.2 (IC 50  = 36.9 ± 4.9 μM) and Kv 1.3 (IC 50  = 115.7 ± 7.3 μM) and in addition, acquired affinity for Kv 1.1 channels (IC 50  = 110.7 ± 7.7 μM). κ-KTx1.3 K20R failed to produce any blockade on the channel subtypes tested. These data suggest that the presence of an additional charged residue in a position adjacent to the dyad lysine impedes the functional block of Kv 1 channels produced by κ-KTx1.3.

Selvanayagam Nirthanan - One of the best experts on this subject based on the ideXlab platform.

  • active sites of spinoxin a potassium channel scorpion toxin elucidated by systematic alanine scanning
    Biochemistry, 2016
    Co-Authors: Steve Peigneur, Selvanayagam Nirthanan, Jan Tytgat, P Gopalakrishnakone, Yoko Yamaguchi, Chihiro Kawano, Takeru Nose, Kazuki Sato
    Abstract:

    Peptide toxins from scorpion venoms constitute the largest group of toxins that target the voltage-gated potassium channel (Kv). Spinoxin (SPX) isolated from the venom of scorpion Heterometrus spinifer is a 34-residue peptide neurotoxin cross-linked by four disulfide bridges. SPX is a potent inhibitor of Kv1.3 potassium channels (IC50 = 63 nM), which are considered to be valid molecular targets in the diagnostics and therapy of various autoimmune disorders and cancers. Here we synthesized 25 analogues of SPX and analyzed the role of each amino acid in SPX using alanine scanning to study its structure–function relationships. All synthetic analogues showed similar disulfide bond pairings and secondary structures as native SPX. Alanine replacements at Lys23, Asn26, and Lys30 resulted in loss of activity against Kv1.3 potassium channels, whereas replacements at Arg7, Met14, Lys27, and Tyr32 also largely reduced inhibitory activity. These results suggest that the side chains of these amino acids in SPX play an...

  • Assignment of voltage-gated potassium channel blocking activity to κ-ktx1.3, a non-toxic homologue of κ-hefutoxin-1, from Heterometrus spinifer venom
    Biochemical pharmacology, 2004
    Co-Authors: Selvanayagam Nirthanan, Joost Pil, Yousra Abdel-mottaleb, Yuko Sugahara, Ponnampalam Gopalakrishnakone, Jeremiah S. Joseph, Kazuki Sato, Jan Tytgat
    Abstract:

    Abstract A new family of weak K + channel toxins (designated κ-KTx) with a novel “bi-helical” scaffold has recently been characterized from Heterometrus fulvipes (Scorpionidae) venom. Based on the presence of the minimum functional dyad (Y5 and K19), κ-hefutoxin-1 (κ-KTx1.1) was investigated and found to block Kv 1.2 (IC 50 ∼40 μM) and Kv 1.3 (IC 50 ∼150 μM) channels. In the present study, κ-KTx1.3, that shares ∼60% identity with κ-hefutoxin 1, has been isolated from Heterometrus spinifer venom. Interestingly, despite the presence of the functional dyad (Y5 and K19), κ-KTx1.3 failed to reproduce the K + channel blocking activity of κ-hefutoxin-1. Since the dyad lysine in κ-KTx1.3 was flanked by another lysine (K20), it was hypothesized that this additional positive charge could hinder the critical electrostatic interactions known to occur between the dyad lysine and the Kv 1 channel selectivity filter. Hence, mutants of κ-KTx1.3, substituting K20 with a neutral (K20A) or a negatively (K20E) or another positively (K20R) charged amino acid were synthesized. κ-KTx1.3 K20E, in congruence with κ-hefutoxin 1 with respect to subtype selectivity and affinity, produced blockade of Kv 1.2 (IC 50  = 36.8 ± 4.9 μM) and Kv 1.3 (IC 50  = 53.7 ± 6.7 μM) but not Kv 1.1 channels. κ-KTx1.3 K20A produced blockade of both Kv 1.2 (IC 50  = 36.9 ± 4.9 μM) and Kv 1.3 (IC 50  = 115.7 ± 7.3 μM) and in addition, acquired affinity for Kv 1.1 channels (IC 50  = 110.7 ± 7.7 μM). κ-KTx1.3 K20R failed to produce any blockade on the channel subtypes tested. These data suggest that the presence of an additional charged residue in a position adjacent to the dyad lysine impedes the functional block of Kv 1 channels produced by κ-KTx1.3.

  • Invited Paper: Animal Toxins of Asia and Australia AUTONOMIC EFFECTS OF SOME SCORPION VENOMS AND TOXINS
    2002
    Co-Authors: Matthew Ce Gwee, Selvanayagam Nirthanan, Ponnampalam Gopalakrishnakone, Hoon Eng Khoo, R. Manjunatha Kini, L. S. Cheah
    Abstract:

    SUMMARY 1. The autonomic effects of venoms and toxins from several species of scorpions, including the Indian red scorpion Mesobuthus tamulus, the Chinese scorpion Buthus martensi Karsch and the Israeli scorpion Leiurus quinquestriatus quinquestriatus, all belonging to Buthidae, and the Asian black scorpions Heterometrus longimanus and Heterometrus spinifer, belonging to Scorpionidae, are reviewed. 2. The effects of the venoms of M. tamulus and L. q. quinquestriatus on noradrenergic and nitrergic transmission in the rat isolated anococcygeus muscle revealed that both venoms mediated their pharmacological effects via a prejunctional mechanism involving the activation of voltage-sensitive sodium channels with consequent release of neurotransmitters that mediate target organ responses, similar to the effects mediated by other � -scorpion toxins. 3. Two new toxins, Makatoxin I and Bukatoxin, were purified to homogeneity from the venom of B. martensi Karsch. Determination of their complete amino acid sequences confirmed that both toxins belonged to the class of � -scorpion toxins. The effects of both toxins on noradrenergic and nitrergic transmission in the rat anococcygeus muscle provided firm evidence that their pharmacological actions also closely resembled those mediated by other � -scorpion toxins on neuronal voltagesensitive sodium channels. 4. The venoms of H. longimanus and H. spinifer were found to have high concentrations of noradrenaline (1.8 � 0.3 mmol/L) and relatively high concentrations of acetylcholine (79.8 � 1.7 � mol/L) together with noradrenaline (146.7 � 19.8 � mol/L), respectively, which can account for their potent direct cholinergic and noradrenergic agonist actions in the rat anococcygeus muscle. 5. Our studies confirmed that the rat anococcygeus muscle is an excellent nerve‐smooth muscle preparation for investigating the effects of bioactive agents on noradrenergic and nitrergic transmission, as well as the direct agonist actions of these agents on post-synaptic � -adrenoceptors and M3 muscarinic cholinoceptors. Although many studies, including our own, have documented that scorpion venoms and toxins mediate their primary effects via a prejunctional mechanism that leads to the marked release of various autonomic neurotransmitters, our studies have shown that there are exceptions

Jiao Guo-bin - One of the best experts on this subject based on the ideXlab platform.