Structural models of the transmembrane region of voltage-gated and other K+ channels in open, closed, and inactivated conformations
Structural models of the transmembrane region of voltage-gated and other K+ channels in open, closed, and inactivated conformations
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DOI：
10.1006/jsbi.1998.3962
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发表时间：
1998-01-01
影响因子：
3
通讯作者：
Guy, HR
中科院分区：
文献类型：
--
作者：
Durell, SR;Hao, YL;Guy, HR
一个涉及许多研究实验室的大型多学科合作努力仍在继续，它使用分子生物学和膜生物物理学的间接方法来分析K（+）通道的三维结构和功能机制。这项工作也延伸到这些通道的远亲，包括电压门控Na（+）和Ca（2+）通道。我们小组在这一过程中所扮演的角色是将实验研究中获得的信息与分子建模技术结合联合收割机，以生成这些蛋白质的原子尺度结构模型。建模过程包括三个阶段，概括为：（I）预测通道序列跨膜拓扑结构，包括片段的功能和二级结构;（II）预测跨膜片段的相对位置，以及（III）填充氨基酸残基的所有原子，具有能量稳定相互作用的构象。生理化学和进化原理（包括序列同源性分析）用于指导开发。除了测试不同结构假设的空间和能量特征外，这些模型还为新实验的设计提供指导。结构建模还可以用来填补实验数据的空白，例如预测其他残基相互作用和负责功能过程的构象变化。建模过程目前处于实验研究已经明确证实了我们早期关于不同片段的跨膜拓扑结构和功能的大部分预测的阶段。此外，这份报告描述了详细的，三维模型，我们已经开发的整个跨膜区和重要的功能位点的电压门控振荡器K（+）通道在开放，关闭，和失活的构象（包括离子选择性孔和电压传感器区域）。作为这一努力的一部分，我们还描述了我们如何为许多其他主要的K（+）通道家族开发结构模型，以帮助确定共同的结构基序。作为一个例子，我们还提出了一个详细的模型，较小的细菌K（+）通道变铅青链霉菌。最后，我们讨论了使用新开发的实验方法来确定这些通道蛋白的结构和分析功能的策略。(C)北京：科学出版社.
A large collaborative, multidisciplinary effort involving many research laboratories continues which uses indirect methods of molecular biology and membrane biophysics to analyze the three-dimensional structures and functional mechanisms of K(+) channels. This work also extends to the distant relatives of these channels, including the voltage-gated Na(+) and Ca(2+) channels. The role that our group plays in this process is to combine the information gained from experimental studies with molecular modeling techniques to generate atomic-scale structural models of these proteins. The modeling process involves three stages which are summarized as: (I) prediction of the channel sequence transmembrane topology, including the functionality and secondary structure of the segments; (II) prediction of the relative positions of the transmembrane segments, and (III) filling in all atoms of the amino acid residues, with conformations for energetically stabilized interactions. Both physiochemical and evolutionary principles (including sequence homology analysis) are used to guide the development. In addition to testing the steric and energetic feasibilities of different structural hypotheses, the models provide guidance for the design of new experiments. Structural modeling also serves to "fill in the gaps" of experimental data, such as predicting additional residue interactions and conformational changes responsible for functional processes. The modeling process is currently at the stage that experimental studies have definitely confirmed most of our earlier predictions about the transmembrane topology and functionality of different segments. Additionally, this report describes the detailed, three-dimensional models we have developed for the entire transmembrane region and important functional sites of the voltage-gated Shaker K(+) channel in the open, closed, and inactivated conformations (including the ion-selective pore and voltage-sensor regions). As part of this effort, we also describe how our development of structural models for many of the other major K(+) channel families aids in determining common structural motifs. As an example, we also present a detailed model of the smaller, bacterial K(+) channel from Streptomyces lividans. Finally, we discuss strategies for using newly developed experimental methods for determining the structures and analyzing the functions of these channel proteins. (C) 1998 Academic Press.