A Key Agonist-induced Conformational Change in the Cannabinoid Receptor CB1 Is Blocked by the Allosteric Ligand Org 27569
A Key Agonist-induced Conformational Change in the Cannabinoid Receptor CB1 Is Blocked by the Allosteric Ligand Org 27569
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DOI：
10.1074/jbc.m112.352328
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发表时间：
2012-09-28
影响因子：
4.8
通讯作者：
Farrens, David L.
中科院分区：
文献类型：
--
作者：
Fay, Jonathan F.;Farrens, David L.
调节G蛋白偶联受体对传统正构药物反应的变构配体是一个令人兴奋和迅速发展的药理学领域。大麻素受体CB1的变构配体Org 27569表现出有趣的效果；它增加激动剂结合，但阻断激动剂诱导的CB1信号传导。在这里，我们探索了这种行为背后的机制，使用位点定向荧光标记方法。我们的研究结果表明，Org 27569阻断了CB1中伴随G蛋白结合和/或激活的构象变化，从而抑制了完全活性CB1结构的形成。这种行为背后的潜在机制是，Org 27569的同时结合产生了一种独特的激动剂结合构象，这种构象可能类似于在受体完全激活途径上形成的中间结构。
Allosteric ligands that modulate how G protein-coupled receptors respond to traditional orthosteric drugs are an exciting and rapidly expanding field of pharmacology. An allosteric ligand for the cannabinoid receptor CB1, Org 27569, exhibits an intriguing effect; it increases agonist binding, yet blocks agonist-induced CB1 signaling. Here we explored the mechanism behind this behavior, using a site-directed fluorescence labeling approach. Our results show that Org 27569 blocks conformational changes in CB1 that accompany G protein binding and/or activation, and thus inhibit formation of a fully active CB1 structure. The underlying mechanism behind this behavior is that simultaneous binding of Org 27569 produces a unique agonist-bound conformation, one that may resemble an intermediate structure formed on the pathway to full receptor activation.