Zarrabi M, Naderi-Manesh H
Department of Biophysics, Faculty of Science, Tarbiat Modares University, Tehran, Iran.
Proteins. 2008 May 15;71(3):1441-9. doi: 10.1002/prot.21833.
Kappa-Hefutoxin1 is a K(+) channel-blocking toxin from the scorpion Heterometrus fluvipes. It is a 22-residue protein that adapts a novel fold of two parallel helices linked by two disulfide bridges without beta-sheets. Recognition of interactions of kappa-Hefutoxin1 with the voltage-gated potassium channels, Kv1.1, Kv1.2, and Kv1.3, was studied by 3D-Dock software package. All structures of kappa-Hefutoxin1 were considered during the simulations, which indicated that even small changes in the structure of kappa-Hefutoxin1 considerably affected both the recognition and the binding between kappa-Hefutoxin1 and the Kv1 channels. kappa-Hefutoxin1 is located around the extracellular part of the Kv1 channels, making contacts with its helices. Lys 19, Tyr 5, Arg 6, Trp 9, or Arg 10 in the toxin and residues Asp 402, His 404, Thr 407,Gly 401, and Asp 386 in each subunit of the Kv potassium channel are the key residues for the toxin-channel recognition. Moreover, the simulation result demonstrates that the hydrophobic interactions are important in interaction of negatively charged toxins with potassium channels. The results of our docking/molecular dynamics simulations indicate that our 3D model structure of the kappa-Hefutoxin1-complex is both reasonable and acceptable and could be helpful for smarter drug design and the blocking agents of Kv1 channels.
κ-赫富毒素1是一种来自蝎子异距蝎的钾通道阻断毒素。它是一种由22个氨基酸组成的蛋白质，具有由两个二硫键连接的两个平行螺旋的新颖折叠结构，没有β-折叠。利用3D-Dock软件包研究了κ-赫富毒素1与电压门控钾通道Kv1.1、Kv1.2和Kv1.3相互作用的识别情况。在模拟过程中考虑了κ-赫富毒素1的所有结构，这表明即使κ-赫富毒素1结构的微小变化也会显著影响κ-赫富毒素1与Kv1通道之间的识别和结合。κ-赫富毒素1位于Kv1通道的细胞外部分周围，与通道的螺旋结构相互接触。毒素中的赖氨酸19、酪氨酸5、精氨酸6、色氨酸9或精氨酸10以及钾通道Kv每个亚基中的天冬氨酸402、组氨酸404、苏氨酸407、甘氨酸401和天冬氨酸386是毒素与通道识别的关键残基。此外，模拟结果表明疏水相互作用在带负电荷的毒素与钾通道的相互作用中很重要。我们对接/分子动力学模拟的结果表明，我们构建的κ-赫富毒素1复合物的三维模型结构是合理且可接受的，可能有助于更智能的药物设计以及Kv1通道阻断剂的研发。
