G protein-coupled receptors (GPCRs) form the largest family of membrane proteins involved in signal transduction. Because of their ability to regulate a wide range of cellular responses and their dysregulation being associated with many diseases, GPCRs remain a key therapeutic target for several clinical indications. In recent years, it has been demonstrated that ligands for a given receptor can engage distinct pathways with different relative efficacies, a concept known as biased signaling or functional selectivity. However, the structural determinants of this phenomenon remain poorly understood. Using the β2-adrenergic receptor as a model, we identified a linker residue (L124^3.43) between the known PIF and NPxxY structural motifs, that plays a central role in the differential efficacy of biased ligands toward the Gs and β-arrestin pathways. Given the high level of conservation of this linker residue, the study provides structural explanations for biased signaling that can be extrapolated to other GPCRs.

中文翻译：

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G蛋白偶联受体信号传导功效和Gs与β-Arrestin之间偏倚的结构洞察

G蛋白偶联受体（GPCR）构成了参与信号转导的最大膜蛋白家族。由于其调节多种细胞应答的能力以及与许多疾病相关的失调，GPCR仍然是几种临床适应症的关键治疗靶标。近年来，已经证明给定受体的配体可以以不同的相对效率参与不同的途径，这一概念被称为偏向信号或功能选择性。但是，这种现象的结构决定因素仍然知之甚少。使用β2-肾上腺素能受体作为模型，我们确定了一个接头残基（L124 ^3.43）在已知的PIF和NPxxY结构基序之间），在偏向Gs和β-arrestin途径的配体的差异功效中起着核心作用。鉴于该接头残基的高度保守性，该研究为可推断到其他GPCR的偏向信号提供了结构性解释。