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首页> 外文期刊>Physical chemistry chemical physics: PCCP >Competitive binding of HIF-1 alpha and CITED2 to the TAZ1 domain of CBP from molecular simulations
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Competitive binding of HIF-1 alpha and CITED2 to the TAZ1 domain of CBP from molecular simulations

机译：HIF-1α和Cited2与分子模拟中CBP的TAZ1结构域的竞争性结合

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Many intrinsically disordered proteins (IDPs) are involved in complex signalling networks inside the cell. Their particular binding modes elicit different types of responses that can be subtly regulated. Here we study the binding of two disordered transactivation domains from proteins HIF-1 alpha and CITED2, whose binding to the TAZ1 domain of CBP is critical for the hypoxic response. Experiments have shown that both IDPs compete for their shared partner, and that this competition is mediated by the formation of a ternary intermediate state. Here we use computer simulations with a coarse-grained model to provide a detailed molecular description of this intermediate. We find that the conserved LP(Q/E)L motif may have a critical role in the displacement of HIF-1 alpha by CITED2 and show a possible mechanism for the transition from the intermediate to the bound state. We also explore the role of TAZ1 dynamics in the binding. The results of our simulations are consistent with many of the experimental observations and provide a detailed view of the emergent properties in the complex binding of these IDPs.
机译：许多本质无序的蛋白质（IDP）涉及细胞内的复杂信号网络。它们的特定绑定模式引出了可以通过巧妙调节的不同类型的响应。在这里，我们研究了来自蛋白质HIF-1α和CitiTe2的两种无序的反椎间膜域的结合，其与CBP的TaZ1结构域的结合对于缺氧反应至关重要。实验表明，IDPS两者都竞争其共享合作伙伴，并且该竞争通过形成三元中级国家进行介绍。在这里，我们使用具有粗粒模型的计算机模拟，以提供这种中间体的详细分子描述。我们发现保守的LP（Q / e）L基质可以在CitiTe2的HIF-1α位移中具有关键作用，并显示从中间到结合状态的过渡的可能机制。我们还探讨了TAZ1动态在绑定中的作用。我们的模拟结果与许多实验观察结果一致，并在这些IDP的复杂结合中提供了紧急性质的详细视图。

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