Molecular basis of α-KTx specificity
Molecular basis of α-KTx specificity
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DOI：
10.1016/j.toxicon.2003.11.029
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发表时间：
2004-06-15
期刊：
影响因子：
2.8
通讯作者：
Mullmann, TJ
中科院分区：
文献类型：
--
作者：
Giangiacomo, KM;Ceralde, Y;Mullmann, TJ
蝎毒中的钾通道抑制剂肽α-KTX，由于其与外孔的高亲和力相互作用，极大地促进了我们对钾通道结构和功能的了解，α-KTX有助于识别构成功能通道的氨基酸和蛋白质。α-KTX对不同的钾通道表现出很大范围的亲和力，结合自由能的差异超过8kcal/mol。这些亲和力的差异是α-KTX特异性的基础，并有助于揭示钾通道的生理和病理生理作用。α-KTX亚家族1-3对MAXI-K通道和K-V通道的特异性有显著差异。然而，许多钾通道在很大程度上不受α-KTX的影响。毒素结合自由能的差异为定义特异性提供了一个定量框架。作为特异度的实用判据，提出了最小结合自由能差为2.72kcal/mol。野生型和突变型毒素和通道的结合自由能差异可以指向潜在的氨基酸特异性和钾通道外孔的独特特征。已知的钾通道的3D结构结合超过60个钾通道的CLUSTALW序列比对，显示了α-KTX结合域的显著变化。基于结构的钾通道与α-KTXS络合的同源模型，结合毒素结合自由能的测定，将进一步加深我们对α-KTX专一性的分子基础的理解。(C)2004爱思唯尔有限公司。保留所有权利。
Potassium channel inhibitor peptides from scorpion venom, alpha-KTx, have greatly advanced our understanding of potassium channel structure and function, Because of their high affinity interaction with the outer pore, alpha-KTx's have aided, in identification of amino acids lining the pore and of proteins constituting functional channels. The alpha-KTx's display a large range of affinities for different potassium channels with differences in binding free energy exceeding similar to 8 kcal/mol. These differences in affinities are the foundation of alpha-KTx specificity and have aided in revealing the physiological and patho-physiological roles of potassium channels. The alpha-KTx subfamilies 1-3, display gross differences in specificity for maxi-K vs. K-V channels. However, many potassium channels are largely untouched by alpha-KTx's. Differences in toxin binding free energy provide a quantitative framework for defining specificity. As a practical criterion for specificity a minimum binding free energy difference of 2.72 kcal/mol is proposed. Binding free energy differences for wild-type and mutant toxins and channels can point to amino acids underlying specificity and to unique features of potassium channel outer pores. Known 3D structures of potassium channels in combination with CLUSTALW sequence alignment of over 60 potassium channels reveal significant variation in alpha-KTx binding domains. Structure-based homology models of potassium channels complexed with alpha-KTxs, in combination with measurements of toxin binding free energy, will further our understanding of the molecular basis of alpha-KTx specificity. (C) 2004 Elsevier Ltd. All rights reserved.