Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Science. 2020 Feb 21;367(6480):881-887. doi: 10.1126/science.aaz0326.
Biased signaling, in which different ligands that bind to the same G protein-coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear, however, hampering efforts to design drugs with desired signaling profiles. Here, we use extensive atomic-level molecular dynamics simulations to determine how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. The receptor adopts two major signaling conformations, one of which couples almost exclusively to arrestin, whereas the other also couples effectively to a G protein. A long-range allosteric network allows ligands in the extracellular binding pocket to favor either of the two intracellular conformations. Guided by this computationally determined mechanism, we designed ligands with desired signaling profiles.
偏向信号传导，即不同配体与相同的 G 蛋白偶联受体结合，优先触发不同的信号通路，为设计更安全、更有效的药物提供了巨大的潜力。然而，其结构机制尚不清楚，这阻碍了设计具有所需信号特征的药物的努力。在这里，我们使用广泛的原子级分子动力学模拟来确定血管紧张素 II 型 1 受体上的偏向信号传导和 G 蛋白偏向信号传导是如何产生的。该受体采用两种主要的信号传导构象，其中一种构象几乎只与抑制蛋白偶联，而另一种构象也与 G 蛋白有效偶联。长程变构网络允许细胞外结合口袋中的配体偏向于两种细胞内构象中的任何一种。根据这种通过计算确定的机制，我们设计了具有所需信号特征的配体。
