Vilardaga Jean-Pierre, Steinmeyer Ralf, Harms Greg S, Lohse Martin J
Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany.
Nat Chem Biol. 2005 Jun;1(1):25-8. doi: 10.1038/nchembio705. Epub 2005 May 24.
G protein-coupled receptors (GPCRs) recognize a wide variety of extracellular ligands to control diverse physiological processes. Compounds that bind to such receptors can either stimulate, fully or partially (full or partial agonists), or reduce (inverse agonists) the receptors' basal activity and receptor-mediated signaling. Various studies have shown that the activation of receptors through binding of agonists proceeds by conformational changes as the receptor switches from a resting to an active state leading to G protein signaling. Yet the molecular basis for differences between agonists and inverse agonists is unclear. These different classes of compounds are assumed to switch the receptors' conformation in distinct ways. It is not known, however, whether such switching occurs along a linear 'on-off' scale or whether agonists and inverse agonists induce different switch mechanisms. Using a fluorescence-based approach to study the alpha2A-adrenergic receptor (alpha(2A)AR), we show that inverse agonists are differentiated from agonists in that they trigger a very distinct mode of a receptor's switch. This switch couples inverse agonist binding to the suppression of activity in the receptor.
G蛋白偶联受体（GPCRs）可识别多种细胞外配体，以控制各种生理过程。与这类受体结合的化合物可以刺激受体，完全或部分地（完全或部分激动剂），或降低（反向激动剂）受体的基础活性和受体介导的信号传导。各种研究表明，激动剂通过结合激活受体是通过构象变化进行的，因为受体从静息状态转变为活性状态，从而导致G蛋白信号传导。然而，激动剂和反向激动剂之间差异的分子基础尚不清楚。假定这些不同类别的化合物以不同方式切换受体的构象。然而，尚不清楚这种切换是否沿着线性的“开-关”尺度发生，或者激动剂和反向激动剂是否诱导不同的切换机制。使用基于荧光的方法研究α2A肾上腺素能受体（α(2A)AR），我们发现反向激动剂与激动剂的区别在于它们触发了受体切换的一种非常独特的模式。这种切换将反向激动剂结合与受体活性的抑制联系起来。
