Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.
J Biol Chem. 2012 Sep 28;287(40):33873-82. doi: 10.1074/jbc.M112.352328. Epub 2012 Jul 30.
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.
变构配体调节 G 蛋白偶联受体对传统正位药物的反应，是药理学中一个令人兴奋且快速发展的领域。大麻素受体 CB1 的一种变构配体 Org 27569 表现出一种有趣的效果；它增加了激动剂的结合，但阻断了激动剂诱导的 CB1 信号转导。在这里，我们使用定点荧光标记方法探索了这种行为背后的机制。我们的结果表明，Org 27569 阻断了伴随 G 蛋白结合和/或激活的 CB1 构象变化，从而抑制了完全激活的 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，可能类似于在完全受体激活途径中形成的中间结构。
