Structure-function relationships of Toll-like receptor domains through homology modelling and molecular dynamics
Structure-function relationships of Toll-like receptor domains through homology modelling and molecular dynamics
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DOI：
10.1042/bst0351515
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发表时间：
2007-12-01
影响因子：
3.9
通讯作者：
Weber, A. N. R.
中科院分区：
文献类型：
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作者：
Kubarenko, A.;Frank, M.;Weber, A. N. R.
TLR（Toll 样受体）是免疫系统的模式识别受体，可根据不同的分子特征识别病原体。尽管同一物种内的不同 TLR（直系同源物）或不同物种间的单个 TLR（同源物）在蛋白质序列上相似，但它们在功能方面存在很大差异，例如在接头选择的配体辨别方面。由于缺乏结构信息，很难对这些现象提供解释。我们将同源建模与能量最小化和分子动力学模拟相结合，以便从结构角度解决这些有趣的生物现象。由此成功生成了人和小鼠TLR3和TLR4结构域的三维模型。除了提供可以解释和设计诱变研究（定点诱变和随机诱变）的结构框架之外，分子动力学还使我们能够在类似溶液的条件下研究和模拟蛋白质结构。我们已将这种方法应用于人类 TLR3 和 TLR4 ECD（胞外域），从而深入了解 TLR ECD 的动态。还讨论了从我们的结构模型得出的其他结论。我们希望我们的结构建模方法可以扩展到 TLR 家族的其他成员或其他信号转导途径，成为设计实验以进一步解决 TLR 生物学问题的宝贵工具。
TLRs (Toll-like receptors) are pattern-recognition receptors of the immune system and recognize pathogens based on distinct molecular signatures. Although different TLRs within the same species (orthologues) or individual TLRs across different species (homologues) are similar in protein sequence, they differ considerably with regard to their function, for example with regard to ligand discrimination of adaptor selection. Owing to the lack of structural information, explanations for these phenomena have been difficult to provide. We have combined homology modelling with energy minimization and Molecular Dynamics simulation in order to address these interesting biological phenomena from a structural angle. Thus three-dimensional models of human and mouse TLR3 and TLR4 domains were successfully generated. Apart from providing a structural framework in which mutagenesis studies (both site-directed and random) can be interpreted and designed, Molecular Dynamics also allowed us to study and simulate protein structure under solution-like conditions. We have applied this approach to the human TLR3 and TLR4 ECDs (ectodomains) providing insights into the dynamics of TLR ECDs. Other conclusions drawn from our structural models are also discussed. We hope that our structural modelling approach, which can be extended to other members of the TLR family or other signal transduction pathways, will serve as a valuable tool for the design of experiments to address questions of TLR biology further.