揭开毒素改变离子通道结构之谜

    德国马克斯•普朗克生物物理化学研究所和德国、法国的研究员们结合磁共振波谱学（固态核磁共振）原理，观察了某些特殊蛋白质的合成过程，希望籍此揭开毒素对钾通道结构改变作用之谜。该研究使进一步开发治疗高血压和其它与钾离子通道失活有关疾病的新药成为可能。

    人体的细胞外有膜，许多由特殊蛋白质构成的离子通道镶嵌其中，仅让特定的离子穿过。这种通道存在电化学梯度，允许神经和心肌细胞的信号通过，当神经或心肌细胞兴奋时，离子通道结构就会发生改变，打开小孔让离子进入。

    就如钾离子通道仅允许钾离子通过一样，不同的通道仅对不同的离子开放。一些有毒动物用非常特殊的毒素侵入目标通道，使毒素堵塞通道导致电信号不能穿越膜——由此经常杀死细胞。此前尽管科学家运用X光结晶学在研究离子通道方面取得了巨大进展，但尚未能从结构水平方面很好地研究这种相互间的作用。

    马克斯•普朗克生物物理化学研究所的研究员和汉堡神经信号处理学院及法国马赛布大学的同行们一起，用一种新的固态核磁共振仪观察特定蛋白质的合成过程和非洲肥尾蝎毒素对离子通道的影响，以确定原子水平上的细菌钾离子通道如何和毒素相互作用。
    研究人员首先检测了已中毒通道蛋白的电生理特征。他们将其中的一些蛋白进行标记并用固态核磁共振仪进行检测（那些有标记的蛋白包含具有内在旋转磁力矩的碳和氮原子，能增强核磁共振的信号）。

    通过对毒素侵袭离子通道前后分光镜数据的分析，发现毒素能附于离子通道的某特定区域（毛孔部位）并改变这个区域的结构。但这种毒素对离子通道的作用只有在它能够识别离子通道中一段特殊的氨基酸序列时才能奏效。

    此外，毒素结合对象固有的可变通性对相互作用也非常重要，因为只有双方能够改变分子结构时，强劲的交互作用才能发生。

    应用这种新的分光镜方法，科学家们现在已能较好地了解钾通道的药理学和生理学特征，为今后开发更好、更具特效的药疗法打开了一扇天窗。

译文源自：Biology/Biochemistry News 16 Apr 2006
Unraveling The Mysteries Of Poison
Main Category: Biology/Biochemistry News
Article Date: 16 Apr 2006

Researchers from the Max Planck Institite for Biophysical Chemistry and other German and French colleagues have combined magnetic resonance spectroscopy (solid-state NMR) with special protein synthesis procedures to uncover how potassium channels and toxins combine and change in structure. This work could make it possible to develop medications for high blood pressure and many other diseases connected to potassium channel failure (Nature, April 2006).

Our body's cells have membranes, and "ion channels" are embedded in them. Ion channels are special proteins which let only certain ions through the membrane. The channels build an electro-chemical gradient, allowing nerve and heart muscle cell signals to pass. The nerve or heart muscle cell is excited, and the ion channel structure changes, developing pores which let the ions through. Different channels are open to different specific ions; for example, potassium channels only allow potassium ions through. Poisonous animals use very specific toxins to target channels; the toxins block the channels and make it impossible for electric signals to move through the membrane - often killing the cell.

These kind of interactions had not been well investigated at a structural level - even though scientists had made great strides studying ion channels, using x-ray crystallography. Scientists from the Max Planck Institute for Biophysical Chemistry in Göttingen, working together with researchers from the Institute for Neural Signal Processing in Hamburg and French colleagues from the University of Marseille, combined a new method of solid-state NMR with particular protein synthesis procedures and looked at the example of poison from the north African scorpion Androctonus mauretanicus mauretanicus, to determine how bacterial potassium channels interact with toxins at an atomic level.

The researchers first examined the electrophysiological characteristics of the "poisoned" channel protein. The scientists "spin-marked" some of them and investigated them with solid-state NMR. Spin-marked proteins contain carbon and nitrogen atoms with an intrinsic magentic moment (spin) which strengthens the NMR's signals. Looking at spectroscopic data before and after the toxin affected the channel, it turned out that the poison attaches to a particular area of the channel - the pore region - and changes the area's structure. The poison is thus only effective when it recognises a particular amino acid sequence in the ion channel. It is also important how intrinsically flexible the binding partner is; for a strong interaction to take place, the molecules of both partners have to be able to change their structures.

Applying these new spectroscopic methods, scientists are now better understanding the pharmacology and physiology of potassium channels. This could lead to better, more specific medications.


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