Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists
Chimeric, mutant orexin receptors show key interactions between orexin receptors, peptides and antagonists
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DOI：
10.1016/j.ejphar.2011.05.074
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发表时间：
2011-09-30
影响因子：
5
通讯作者：
Sutton, Steven W.
中科院分区：
文献类型：
--
作者：
Da-Thao Tran;Bonaventure, Pascal;Sutton, Steven W.
食欲素受体拮抗剂正在被研究为治疗失眠和成瘾障碍的药物。本研究探讨了食欲素受体(食欲素1受体和食欲素2受体)、食欲素肽和小分子食欲素拮抗剂之间的相互作用。为了研究这些现象，制作了各种突变型增食欲素受体，并通过受体结合和功能分析进行了测试。两种食欲素受体的结构域被交换以显示食欲素肽和代表性的选择性食欲素受体拮抗剂的关键配基结合域。增食欲素受体之间结构域交换的结果表明，跨膜区3对于受体与小分子拮抗剂的相互作用至关重要。这些数据还表明，增食欲素多肽占据了更大的足迹，与跨膜区1、氨基末端和跨膜区5以及跨膜区3相互作用。跨膜区3已被证明是视紫红质和β2肾上腺素能受体共同的小分子结合口袋的重要组成部分。根据G蛋白偶联受体晶体结构文献中显示的受体跨膜区的共同排列，以及增食欲素2受体残基苏氨酸135对2增食欲素受体配体选择性的影响，进行额外的增食欲素受体2点突变。这些数据支持食欲素受体结合口袋的模型，在该模型中，跨膜区3和5是配体结合和功能活性的重要贡献者。这些数据还说明了这些受体的共识小分子口袋中配体相互作用的关键接触点。(C)2011年爱思唯尔。版权所有。
Orexin receptor antagonists are being investigated as therapeutic agents for insomnia and addictive disorders. In this study the interactions between the orexin receptors (orexin 1 receptor and orexin 2 receptor), orexin peptides, and small molecule orexin antagonists were explored. To study these phenomena, a variety of mutant orexin receptors was made and tested using receptor binding and functional assays. Domains of the two orexin receptors were exchanged to show the critical ligand binding domains for orexin peptides and representative selective orexin receptor antagonists. Results from domain exchanges between the orexin receptors suggest that transmembrane domain 3 is crucially important for receptor interactions with small molecule antagonists. These data also suggest that the orexin peptides occupy a larger footprint, interacting with transmembrane domain 1, the amino terminus and transmembrane domain 5 as well as transmembrane domain 3. Transmembrane domain 3 has been shown to be an important part of the small molecule binding pocket common to rhodopsin and beta 2-adrenergic receptors. Additional orexin receptor 2 point mutations were made based on the common arrangement of receptor transmembrane domains shown in the G-protein coupled receptor crystal structure literature and the impact of orexin 2 receptor residue threonine 135 on the ligand selectivity of the 2 orexin receptors. These data support a model of the orexin receptor binding pocket in which transmembrane domains 3 and 5 are prominent contributors to ligand binding and functional activity. The data also illustrate key contact points for ligand interactions in the consensus small molecule pocket of these receptors. (C) 2011 Elsevier By. All rights reserved.