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Molecular basis of β-arrestin coupling to formoterol-bound β1-adrenoceptor
Nature ( IF 50.5 ) Pub Date : 2020-06-17 , DOI: 10.1038/s41586-020-2419-1
Yang Lee 1 , Tony Warne 1 , Rony Nehmé 1, 2 , Shubhi Pandey 3 , Hemlata Dwivedi-Agnihotri 3 , Madhu Chaturvedi 3 , Patricia C Edwards 1 , Javier García-Nafría 4, 5 , Andrew G W Leslie 1 , Arun K Shukla 3 , Christopher G Tate 1
Affiliation  

The β1-adrenoceptor (β1AR) is a G-protein-coupled receptor (GPCR) that couples1 to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of β-arrestin 1 (βarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins—known as biased agonism3—is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the β1AR–βarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound β1AR coupled to the G-protein-mimetic nanobody6 Nb80. βarr1 couples to β1AR in a manner distinct to that7 of Gs coupling to β2AR—the finger loop of βarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal α5 helix of Gs. The conformation of the finger loop in βarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin8. β1AR coupled to βarr1 shows considerable differences in structure compared with β1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of β1AR, and find that formoterol has a lower affinity for the β1AR–βarr1 complex than for the β1AR–Gs complex. The structural differences between these complexes of β1AR provide a foundation for the design of small molecules that could bias signalling in the β-adrenoceptors. A cryo-electron microscopy structure of the β1-adrenoceptor coupled to β-arrestin 1 and activated by the biased agonist formoterol, as well as the crystal structure of a related formoterol-bound adrenoreceptor, provide insights into biased signalling in these systems.

中文翻译:

β-抑制素与福莫特罗结合的β1-肾上腺素受体偶联的分子基础

β1-肾上腺素受体 (β1AR) 是一种 G 蛋白偶联受体 (GPCR),可将 1 与异源三聚体 G 蛋白 Gs 偶联。G 蛋白介导的信号传导通过 GPCR 激酶 (GRK) 对受体 C 末端的磷酸化和通过偶联 β-arrestin 1 (βarr1,也称为抑制蛋白 2) 而终止,后者取代 Gs 并通过 MAP 诱导信号传导激酶途径2。合成激动剂优先通过 G 蛋白或抑制素诱导信号传导的能力(称为偏向激动 3)在药物开发中很重要,因为治疗效果可能仅来自一个信号级联,而其他途径可能介导不良副作用 4。要了解抑制素偶联的分子基础,在这里,我们确定了与偏向激动剂福莫特罗 5 结合的脂质纳米盘中 β1AR-βarr1 复合物的低温电子显微镜结构,以及与 G 蛋白模拟纳米抗体 6 Nb80 偶联的福莫特罗结合 β1AR 的晶体结构。βarr1 与 β1AR 偶联的方式与 Gs 与 β2AR 偶联的方式不同——βarr1 的指环在细胞内表面占据更窄的裂缝,与受体的 C 端 α5 螺旋相比,更接近受体的跨膜螺旋 H7 GS。βarr1中指环的构象不同于视觉抑制蛋白的指环与视紫红质8偶联时所采用的构象。与 βarr1 偶联的 β1AR 与与 Nb80 偶联的 β1AR 相比,在结构上显示出相当大的差异,包括细胞外环 3 的向内移动以及 H5 和 H6 的细胞质末端。我们观察到福莫特罗与 β1AR 正构结合位点 H5 中的两个丝氨酸残基之间的相互作用减弱,并发现福莫特罗对 β1AR-βarr1 复合物的亲和力低于对 β1AR-Gs 复合物的亲和力。这些 β1AR 复合物之间的结构差异为设计可能偏向 β-肾上腺素受体信号传导的小分子提供了基础。与 β-arrestin 1 偶联并由偏向激动剂福莫特罗激活的 β1-肾上腺素受体的低温电子显微镜结构,以及相关的福莫特罗结合肾上腺素受体的晶体结构,提供了对这些系统中偏向信号传导的见解。并发现福莫特罗对 β1AR-βarr1 复合物的亲和力低于对 β1AR-Gs 复合物的亲和力。这些 β1AR 复合物之间的结构差异为设计可能偏向 β-肾上腺素受体信号传导的小分子提供了基础。与 β-arrestin 1 偶联并由偏向激动剂福莫特罗激活的 β1-肾上腺素受体的低温电子显微镜结构,以及相关的福莫特罗结合肾上腺素受体的晶体结构,提供了对这些系统中偏向信号传导的见解。并发现福莫特罗对 β1AR-βarr1 复合物的亲和力低于对 β1AR-Gs 复合物的亲和力。这些 β1AR 复合物之间的结构差异为设计可能偏向 β-肾上腺素受体信号传导的小分子提供了基础。与 β-arrestin 1 偶联并由偏向激动剂福莫特罗激活的 β1-肾上腺素受体的低温电子显微镜结构,以及相关的福莫特罗结合肾上腺素受体的晶体结构,提供了对这些系统中偏向信号传导的见解。
更新日期:2020-06-17
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