Characterizing and predicting the functional and conformational diversity of seven-transmembrane proteins
Characterizing and predicting the functional and conformational diversity of seven-transmembrane proteins
复制标题
DOI：
10.1016/j.ymeth.2011.12.005
复制
发表时间：
2011-12-01
期刊：
影响因子：
4.8
通讯作者：
Goddard, William A., III
中科院分区：
文献类型：
--
作者：
Abrol, Ravinder;Kim, Soo-Kyung;Goddard, William A., III
七跨膜受体（7 TMR）的激活允许细胞感知其环境并将细胞外信号（如激素结合）转化为细胞内信号（通过G蛋白偶联和/或抑制蛋白偶联途径）。单个7 TMR能够通过与这些途径偶联来转导细胞内的广谱生理反应。这种细胞内多效性作用是通过这些受体表现出的多种构象实现的。膜蛋白结构测定技术的发展导致许多7 TMR的晶体结构迅速增加。这些受体中的大多数已经以其非活性构象结晶，并且对于一些，许多活性构象之一也已经结晶。考虑到脂质双层的拓扑约束，其导致由大多数非结构化环连接的7个几乎平行的TM螺旋的单倍，这些结构不仅在受体上而且在具有功能活性构象之一的结构的受体的不同功能形式上表现出构象的多样性。在这里，我们提出了一种方法来表征这种构象多样性的跨膜螺旋拓扑结构（TMHTOP）参数，以及如何使用这些螺旋取向参数来预测这些受体的功能不同的多种构象。TMHTOP参数能够量化7 TMR激活的基础结构变化，也揭示了这些受体的多效性的独特机制。它提供了一种通用语言来描述7 TMR激活机制以及在视觉直观的结构参数方面的许多受体之间的差异。蛋白质结构预测方法可以使用这些参数来描述7 TMR构象系综，其与实验数据相结合可以用于开发7 TMR功能的结构基础的可检验假设。(C)2011 Elsevier Inc. All rights reserved.
The activation of seven-transmembrane receptors (7TMRs) allows cells to sense their environment and convert extracellular signals (like hormone binding) into intracellular signals (through G protein-coupled and/or arrestin-coupled pathways). A single 7TMR is capable of transducing a wide spectrum of physiological responses inside a cell by coupling to these pathways. This intracellular pleiotropic action is enabled by multiple conformations exhibited by these receptors. Developments in membrane protein structure determination technologies have led to a rapid increase in crystal structures for many 7TMRs. Majority of these receptors have been crystallized in their inactive conformation and, for some, one of the many active conformations has also been crystallized. Given the topological constraints of a lipid bilayer that results in a single fold of seven almost parallel TM helices connected by mostly unstructured loops, these structures exhibit a diversity of conformations not only across the receptors but also across the different functional forms for receptors with structures for one of the functionally active conformations. Here we present a method to characterize this conformational diversity in terms of transmembrane helix topology (TMHTOP) parameters and how to use these helix orientation parameters to predict functionally-distinct multiple conformations for these receptors. The TMHTOP parameters enable a quantification of the structural changes that underlie 7TMR activation and also sheds a unique mechanistic light on the pleiotropic nature of these receptors. It provides a common language to describe the 7TMR activation mechanisms as well as differences across many receptors in terms of visually intuitive structural parameters. Protein structure prediction methods can use these parameters to describe 7TMR conformational ensembles, which coupled to experimental data can be used to develop testable hypotheses for the structural basis of 7TMR functions. (C) 2011 Elsevier Inc. All rights reserved.