Picard Louis-Philippe, Schonegge Anne-Marie, Bouvier Michel
Department of Biochemistry and Molecular Medicine, Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
ACS Pharmacol Transl Sci. 2019 Apr 3;2(3):148-154. doi: 10.1021/acsptsci.9b00012. eCollection 2019 Jun 14.
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) 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.
G蛋白偶联受体（GPCRs）构成了参与信号转导的最大膜蛋白家族。由于它们能够调节广泛的细胞反应，且其失调与多种疾病相关，GPCRs仍然是多种临床适应症的关键治疗靶点。近年来，已证明给定受体的配体可以通过不同的相对效力参与不同的信号通路，这一概念被称为偏向性信号传导或功能选择性。然而，这一现象的结构决定因素仍知之甚少。我们以β2肾上腺素能受体为模型，在已知的PIF和NPxxY结构基序之间鉴定出一个连接残基（L124），它在偏向性配体对Gs和β-抑制蛋白信号通路的不同效力中起核心作用。鉴于此连接残基的高度保守性，该研究为可外推至其他GPCRs的偏向性信号传导提供了结构解释。
