Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Science. 2012 Mar 2;335(6072):1106-10. doi: 10.1126/science.1215802. Epub 2012 Jan 19.
Extracellular ligand binding to G protein-coupled receptors (GPCRs) modulates G protein and β-arrestin signaling by changing the conformational states of the cytoplasmic region of the receptor. Using site-specific (19)F-NMR (fluorine-19 nuclear magnetic resonance) labels in the β(2)-adrenergic receptor (β(2)AR) in complexes with various ligands, we observed that the cytoplasmic ends of helices VI and VII adopt two major conformational states. Changes in the NMR signals reveal that agonist binding primarily shifts the equilibrium toward the G protein-specific active state of helix VI. In contrast, β-arrestin-biased ligands predominantly impact the conformational states of helix VII. The selective effects of different ligands on the conformational equilibria involving helices VI and VII provide insights into the long-range structural plasticity of β(2)AR in partial and biased agonist signaling.
细胞外配体与 G 蛋白偶联受体 (GPCR) 的结合通过改变受体胞质区域的构象状态来调节 G 蛋白和β-arrestin 信号。使用β(2)-肾上腺素能受体 (β(2)AR) 与各种配体形成的复合物中的特异性 (19)F-NMR (氟-19 核磁共振) 标记物，我们观察到，螺旋 VI 和 VII 的胞质末端采用两种主要构象状态。NMR 信号的变化表明，激动剂结合主要将平衡向螺旋 VI 的 G 蛋白特异性活性状态转移。相比之下，β-arrestin 偏向配体主要影响螺旋 VII 的构象状态。不同配体对涉及螺旋 VI 和 VII 的构象平衡的选择性影响提供了对β(2)AR 在部分和偏向激动剂信号转导中长程结构可塑性的深入了解。
