Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization and affecting various downstream signalling pathways^1,2. Although there is a wealth of structural information detailing the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-electron microscopy structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human β-arrestin 1 (βarr1(ΔCT)). We find that phosphorylation of NTSR1 is critical for the formation of a stable complex with βarr1(ΔCT), and identify phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observe a phosphatidylinositol-4,5-bisphosphate molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared with a structure of a rhodopsin–arrestin-1 complex, in our structure arrestin is rotated by approximately 85° relative to the receptor. These findings highlight both conserved aspects and plasticity among arrestin–receptor interactions.

Arrestin 蛋白与活性磷酸化 G 蛋白偶联受体 (GPCR) 结合，从而阻止 G 蛋白偶联、触发受体内化并影响各种下游信号传导通路^1,2 。尽管有大量的结构信息详细描述了 GPCR 和 G 蛋白之间的相互作用，但关于抑制蛋白如何与 GPCR 结合却知之甚少。在此，我们报道了全长人神经降压素受体 1 (NTSR1) 与截短的人 β-arrestin 1 (βarr1(ΔCT)) 复合物的冷冻电子显微镜结构。我们发现 NTSR1 的磷酸化对于与 βarr1(ΔCT) 形成稳定复合物至关重要，并确定了第三细胞内环和 C 末端可能促进这种相互作用的磷酸化位点。此外，我们观察到磷脂酰肌醇-4,5-二磷酸分子在 NTSR1 跨膜片段 1 和 4 的膜侧与视紫红质抑制蛋白的 C 叶之间形成桥梁。与视紫红质-arrestin-1复合物的结构相比，在我们的结构中，arrestin相对于受体旋转了大约85°。这些发现强调了抑制蛋白-受体相互作用中的保守性和可塑性。