Unique mechanism of the interaction between honey bee toxin TPNQ and rKir1.1 potassium channel explored by computational simulations: insights into the relative insensitivity of channel towards animal toxins.
Unique mechanism of the interaction between honey bee toxin TPNQ and rKir1.1 potassium channel explored by computational simulations: insights into the relative insensitivity of channel towards animal toxins.
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DOI：
10.1371/journal.pone.0067213
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wu Y
中科院分区：
文献类型：
--
作者：
Hu J;Qiu S;Yang F;Cao Z;Li W;Wu Y
21残基紧致型terapin - q （TPNQ）毒素是蜜蜂毒素terapin （TPN）的衍生物，是一种有效的内流K+通道亚型大鼠Kir1.1 （rKir1.1）通道阻断剂，其相互作用机制尚不清楚。基于钾通道塔的柔性特性，建立了一个良好的起始rKir1.1通道结构，用于rKir1.1通道塔对TPNQ毒素的可及性。结合实验丙氨酸扫描诱变数据，进一步利用计算方法获得了与已知动物毒素与钾离子通道结合模式完全不同的TPNQ毒素- rkir1.1通道复合物结构。TPNQ毒素主要以其螺旋结构域作为通道相互作用表面，并以His12作为孔阻断残基。重要的Gln13残基主要与靠近选择性滤波器的通道残基接触，Lys20残基被通道转塔中由Arg118、Thr119、Glu123和Asn124组成的极性“槽”所包围。另一方面，rKir1.1通道的四个炮塔聚集在一起，形成一个狭窄的孔入口通道，用于TPNQ毒素识别。通道孔区域的Phe146和Phe148残基形成了强烈的疏水突起，并与毒素残基产生了显性的非极性相互作用。rKir1.1通道前庭的这些特定结构特征与强效TPNQ毒素的结合很好地匹配，可能限制了经典动物毒素的结合。TPNQ毒素-rKir1.1通道复合物结构不仅揭示了它们独特的相互作用机制，还将揭示动物毒素-钾通道相互作用的多样性，阐明rKir1.1通道对动物毒素的相对不敏感。
The 21-residue compact tertiapin-Q (TPNQ) toxin, a derivative of honey bee toxin tertiapin (TPN), is a potent blocker of inward-rectifier K+ channel subtype, rat Kir1.1 (rKir1.1) channel, and their interaction mechanism remains unclear. Based on the flexible feature of potassium channel turrets, a good starting rKir1.1 channel structure was modeled for the accessibility of rKir1.1 channel turrets to TPNQ toxin. In combination with experimental alanine scanning mutagenesis data, computational approaches were further used to obtain a reasonable TPNQ toxin-rKir1.1 channel complex structure, which was completely different from the known binding modes between animal toxins and potassium channels. TPNQ toxin mainly adopted its helical domain as the channel-interacting surface together with His12 as the pore-blocking residue. The important Gln13 residue mainly contacted channel residues near the selectivity filter, and Lys20 residue was surrounded by a polar “groove” formed by Arg118, Thr119, Glu123, and Asn124 in the channel turret. On the other hand, four turrets of rKir1.1 channel gathered to form a narrow pore entryway for TPNQ toxin recognition. The Phe146 and Phe148 residues in the channel pore region formed strong hydrophobic protrusions, and produced dominant nonpolar interactions with toxin residues. These specific structure features of rKir1.1 channel vestibule well matched the binding of potent TPNQ toxin, and likely restricted the binding of the classical animal toxins. The TPNQ toxin-rKir1.1 channel complex structure not only revealed their unique interaction mechanism, but also would highlight the diverse animal toxin-potassium channel interactions, and elucidate the relative insensitivity of rKir1.1 channel towards animal toxins.
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