Toward an understanding of agonist binding to human Orexin-1 and Orexin-2 receptors with G-protein-coupled receptor modeling and site-directed mutagenesis.
Toward an understanding of agonist binding to human Orexin-1 and Orexin-2 receptors with G-protein-coupled receptor modeling and site-directed mutagenesis.
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DOI：
10.1021/bi401119m
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发表时间：
2013-11-19
期刊：
影响因子：
2.9
通讯作者：
Biggin, Philip C.
中科院分区：
文献类型：
--
作者：
Heifetz, Alexander;Barker, Oliver;Morris, G. Benjamin;Law, Richard J.;Slack, Mark;Biggin, Philip C.
A类G蛋白偶联受体(GPCRs)食欲素-1(OX1)和食欲素-2(OX2)主要位于大脑中，与一系列不同的生理功能有关，包括控制摄食、能量代谢、神经内分泌功能的调节和睡眠-觉醒周期的调节。OX1和OX2的天然激动剂是两种神经肽，即食欲素-A和食欲素-B，它们对这两种受体都有活性。定点突变(SDM)在受体和多肽上都已有报道，并为揭示激动剂活性的关键特征提供了重要的见解。然而，对这些数据是如何联系在一起的结构性解释仍然缺乏。在这项工作中，我们产生并使用SDM数据、同源建模和MD模拟，以及系综-柔性对接来生成OX受体中增食欲素肽的结合姿势，以使SDM数据合理化。我们还开发了一种蛋白质成对相似性比较方法(PROS)和GPCR相似性评估分数(GRAS)，以探索分子动力学模拟中产生的结构数据，并帮助区分不同的GPCR亚状态。结果表明，这些新开发的GPCRs结构评估方法可以用来提供神经肽-食欲素受体相互作用的工作模型。
The class A G-protein-coupled receptors (GPCRs) Orexin-1 (OX1) and Orexin-2 (OX2) are located predominantly in the brain and are linked to a range of different physiological functions, including the control of feeding, energy metabolism, modulation of neuro-endocrine function, and regulation of the sleep–wake cycle. The natural agonists for OX1 and OX2 are two neuropeptides, Orexin-A and Orexin-B, which have activity at both receptors. Site-directed mutagenesis (SDM) has been reported on both the receptors and the peptides and has provided important insight into key features responsible for agonist activity. However, the structural interpretation of how these data are linked together is still lacking. In this work, we produced and used SDM data, homology modeling followed by MD simulation, and ensemble-flexible docking to generate binding poses of the Orexin peptides in the OX receptors to rationalize the SDM data. We also developed a protein pairwise similarity comparing method (ProS) and a GPCR-likeness assessment score (GLAS) to explore the structural data generated within a molecular dynamics simulation and to help distinguish between different GPCR substates. The results demonstrate how these newly developed methods of structural assessment for GPCRs can be used to provide a working model of neuropeptide–Orexin receptor interaction.
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