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钾离子通道蛋白KcsA晶体结构作为钠离子通道孔分子模型的框架。

KcsA crystal structure as framework for a molecular model of the Na(+) channel pore.

作者信息

Lipkind G M, Fozzard H A

机构信息

Cardiac Electrophysiology Labs, Department of Biochemistry & Molecular Biology and Neurobiology, Pharmacology and Physiology, The University of Chicago, Chicago, Illinois 60637, USA.

出版信息

Biochemistry. 2000 Jul 18;39(28):8161-70. doi: 10.1021/bi000486w.

Abstract

The crystal structure of the pore-forming part of the KcsA bacterial K(+)-selective channel suggests a possible motif for related voltage-gated channels. We examined the hypothesis that the spacial orientation of the KcsA M1 and M2 alpha-helices also predicts the backbone location of S5 and S6 helices of the voltage-gated Na(+) channel. That channel's P region structure is expected to be different because selectivity is determined by side-chain interactions rather than by main-chain carbonyls, and its outer vestibule accommodates relatively large toxin molecules, tetrodotoxin (TTX) and saxitoxin (STX), which interact with selectivity ring residues. The Na(+) channel P loop was well-modeled by the alpha-helix-turn-beta-strand motif, which preserves the relationships for toxin interaction with the Na(+) channel found experimentally. This outer vestibule was docked into the extracellular part of the inverted teepee structure formed by the S5 and S6 helices that were spacially located by coordinates of the KcsA M1 and M2 helix main chains [Doyle et al. (1998) Science 280, 69-74], but populated with side chains of the respective S5 and S6 structures. van der Waals contacts were optimized with minimal adjustment of the S5, S6, and P loop structures, forming a densely packed pore structure. Nonregular external S5-P and P-S6 segments were not modeled here, except the P-S6 segment of domain II. The resulting selectivity region structure is consistent with Na(+) channel permeation properties, offering suggestions for the molecular processes involved in selectivity. The ability to construct a Na(+) channel pore model consistent with most of the available biophysical and mutational information suggests that the KcsA structural framework may be conserved in voltage-gated channels.

摘要

KcsA 细菌钾离子选择性通道的成孔部分的晶体结构为相关电压门控通道提供了一种可能的基序。我们检验了这样一种假说,即 KcsA 的 M1 和 M2 α 螺旋的空间取向也能预测电压门控钠离子通道 S5 和 S6 螺旋的主链位置。预计该通道的 P 区结构会有所不同,因为选择性是由侧链相互作用而非主链羰基决定的,并且其外部前庭可容纳相对较大的毒素分子,即河豚毒素(TTX)和石房蛤毒素(STX),它们与选择性环残基相互作用。钠离子通道的 P 环可以很好地用 α 螺旋 - 转角 - β 链基序来模拟,该基序保留了实验中发现的毒素与钠离子通道相互作用的关系。这个外部前庭被对接至由 S5 和 S6 螺旋形成的倒锥形结构的细胞外部分,这些螺旋的空间位置是根据 KcsA 的 M1 和 M2 螺旋主链的坐标确定的[多伊尔等人(1998 年),《科学》280 卷,69 - 74 页],但填充的是各自 S5 和 S6 结构的侧链。通过对 S5、S6 和 P 环结构进行最小程度的调整来优化范德华接触,形成了一个紧密堆积的孔结构。这里没有对不规则的外部 S5 - P 和 P - S6 片段进行建模,除了结构域 II 的 P - S6 片段。所得的选择性区域结构与钠离子通道的通透特性一致,为选择性所涉及的分子过程提供了建议。构建一个与大多数现有生物物理和突变信息一致的钠离子通道孔模型的能力表明,KcsA 的结构框架可能在电压门控通道中得以保留。

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