Arrestins comprise a family of signal regulators of G-protein-coupled receptors (GPCRs), which include arrestins 1 to 4. While arrestins 1 and 4 are visual arrestins dedicated to rhodopsin, arrestins 2 and 3 (Arr2 and Arr3) are β-arrestins known to regulate many nonvisual GPCRs. The dynamic and promiscuous coupling of Arr2 to nonvisual GPCRs has posed technical challenges to tackle the basis of arrestin binding to GPCRs. Here we report the structure of Arr2 in complex with neurotensin receptor 1 (NTSR1), which reveals an overall assembly that is strikingly different from the visual arrestin-rhodopsin complex by a 90° rotation of Arr2 relative to the receptor. In this new configuration, intracellular loop 3 (ICL3) and transmembrane helix 6 (TM6) of the receptor are oriented toward the N-terminal domain of the arrestin, making it possible for GPCRs that lack the C-terminal tail to couple Arr2 through their ICL3. Molecular dynamics simulation and crosslinking data further support the assembly of the Arr2‒NTSR1 complex. Sequence analysis and homology modeling suggest that the Arr2‒NTSR1 complex structure may provide an alternative template for modeling arrestin-GPCR interactions.

中文翻译：

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与 G 蛋白偶联受体结合的逮捕蛋白 2 的复杂结构。

Arrestins 包含 G 蛋白偶联受体 (GPCR) 的信号调节剂家族，其中包括抑制蛋白 1 至 4。虽然抑制蛋白 1 和 4 是视紫红质专用的视觉抑制蛋白，但抑制蛋白 2 和 3（Arr2 和 Arr3）是 β-抑制蛋白已知可调节许多非视觉 GPCR。Arr2 与非视觉 GPCR 的动态和混杂耦合对解决抑制蛋白与 GPCR 结合的基础提出了技术挑战。在这里，我们报告了 Arr2 与神经降压素受体 1 (NTSR1) 复合的结构，该结构通过 Arr2 相对于受体的 90° 旋转，揭示了与视觉抑制素-视紫红质复合物显着不同的整体组装。在这种新配置中，受体的细胞内环 3 (ICL3) 和跨膜螺旋 6 (TM6) 朝向抑制蛋白的 N 端结构域，使缺少 C 末端尾部的 GPCR 可以通过其 ICL3 耦合 Arr2。分子动力学模拟和交联数据进一步支持 Arr2-NTSR1 复合物的组装。序列分析和同源性建模表明，Arr2-NTSR1 复杂结构可以为抑制蛋白-GPCR 相互作用建模提供替代模板。