Exploring the Odorant Binding Site of a G-Protein-Coupled Olfactory Receptor
Exploring the Odorant Binding Site of a G-Protein-Coupled Olfactory Receptor
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DOI：
10.2174/157340908784533247
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发表时间：
2008-05
期刊：
影响因子：
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通讯作者：
Sayako Katada;T. Hirokawa;K. Touhara
中科院分区：
文献类型：
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作者：
Sayako Katada;T. Hirokawa;K. Touhara
嗅觉系统具有复杂的分子机制来识别和区分大量的气味。哺乳动物中气味的检测由数百种嗅觉受体（OR）介导，其包括基因组中最大的G蛋白偶联受体（GPCR）超家族。由于GPCR是治疗应用的主要靶点，因此可在一些GPCR上获得充足的实验数据和计算机建模研究。然而，尽管OR代表所有GPCR的大约一半，但很少对OR进行结构和功能研究。在这里，我们回顾了最近的研究基础上的分子识别的大量气味的OR的机制。结合计算和实验的方法已经揭示了气味的结合部位的OR。基于气味结合模式的气味结合位点的点突变导致配体特异性和拮抗剂活性的预测变化，证明了结合位点模型的有效性，并表明其可应用于OR有用配体的设计。了解嗅觉系统辨别能力的分子基础也将为如何设计GPCR的激动剂或拮抗剂提供见解。
The olfactory system has sophisticated molecular mechanisms for recognizing and discriminating an enormous number of odorants. The detection of odorants in mammals is mediated by several hundreds of olfactory receptors (ORs), which comprise the largest superfamily of G-protein-coupled receptors (GPCRs) in the genome. Because GPCRs are major targets for therapeutic application, ample experimental data and computer modeling studies are available on some GPCRs. However, even though ORs represent approximately one half of all GPCRs, few structural and functional studies have been carried out for ORs. Here, we review recent studies on mechanisms underlying the molecular recognition of a large number of odorants by ORs. A combination of computational and experimental approaches has revealed the odorant- binding site of ORs. Point mutations in the odorant binding site based on the mode of odorant binding resulted in predicted changes in ligand specificity and antagonist activity, demonstrating the validity of the binding site model and indicating that it may be applied to the design of useful ligands for ORs. Understanding the molecular basis for the discriminative power of the olfactory system will also provide insight into how to design agonists or antagonists of GPCRs.