Choosing the drug to fit the protein Many approved drugs bind to G protein–coupled receptors (GPCRs). A challenge in targeting GPCRs is that different ligands preferentially activate different signaling pathways. Two papers show how biased signaling arises for the angiotensin II type 1 receptor that couples to two signaling partners (G proteins and arrestins). Suomivuori et al. used large-scale atomistic simulations to show that coupling to the two pathways is through two distinct GPCR conformations and that extracellular ligands favor one or the other conformation. Wingler et al. present crystal structures of the same receptor bound to ligands with different bias profiles. These structures show conformational changes in and around the binding pocket that match those observed in simulations. This work could provide a framework for the rational design of drugs that are more effective and have fewer side effects. Science, this issue p. 881, p. 888 Atomic-level molecular dynamics reveals how arrestin bias and G protein bias arise at the angiotensin II type 1 receptor. 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.

中文翻译：

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原型 G 蛋白偶联受体中偏向信号的分子机制

选择适合蛋白质的药物 许多批准的药物与 G 蛋白偶联受体 (GPCR) 结合。靶向 GPCR 的一个挑战是不同的配体优先激活不同的信号通路。两篇论文展示了血管紧张素 II 1 型受体如何与两个信号伙伴（G 蛋白和抑制素）偶联的偏向信号发生。索米沃里等人。使用大规模原子模拟来表明通过两种不同的 GPCR 构象与两种途径的耦合，并且细胞外配体有利于一种或另一种构象。温格勒等人。呈现与具有不同偏向特征的配体结合的相同受体的晶体结构。这些结构显示出与模拟中观察到的相匹配的结合口袋内部和周围的构象变化。这项工作可以为合理设计更有效且副作用更少的药物提供一个框架。科学，这个问题 p。881 页。888 原子级分子动力学揭示了血管紧张素 II 1 型受体如何产生抑制蛋白偏倚和 G 蛋白偏倚。偏向信号，即与相同 G 蛋白偶联受体结合的不同配体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广阔的前景。然而，其结构机制仍不清楚，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 1 型受体如何产生抑制素偏差和 G 蛋白偏差。受体采用两种主要的信号构象，其中一个几乎完全与抑制蛋白偶联，而另一个也有效地与 G 蛋白偶联。远程变构网络允许细胞外结合口袋中的配体有利于两种细胞内构象中的任何一种。在这种计算确定的机制的指导下，我们设计了具有所需信号特征的配体。