The neurotensin receptor 1 (NTS₁) is a G protein-coupled receptor (GPCR) with promise as a drug target for the treatment of pain, schizophrenia, obesity, addiction, and various cancers. A detailed picture of the NTS₁ structural landscape has been established by X-ray crystallography and cryo-EM and yet, the molecular determinants for why a receptor couples to G protein versus arrestin transducers remain poorly defined. We used ¹³C^ϵH₃-methionine NMR spectroscopy to show that phosphatidylinositol-4,5-bisphosphate (PIP2) promotes transducer complexation not by dramatically altering the receptor structure but by strengthening long-range allosteric connections, in the form of correlated conformational kinetics, between the orthosteric pocket and highly-conserved activation motifs. β-arrestin-1 further remodels the receptor ensemble by reducing conformational exchange kinetics for a subset of resonances, whereas G protein coupling has little to no effect on the rate. A β-arrestin biased allosteric modulator transforms the NTS1:G protein complex into a concatenation of substates, without triggering transducer dissociation, suggesting that it may function by stabilizing signaling incompetent G protein conformations such as the non-canonical state. Together, our work demonstrates the importance of kinetic information to a complete picture of the GPCR activation landscape.

中文翻译：

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神经降压素受体 1 (NTS1) 变构和信号偏差的动态特性

神经降压素受体 1 (NTS ₁ ) 是一种 G 蛋白偶联受体 (GPCR)，有望作为治疗疼痛、精神分裂症、肥胖、成瘾和各种癌症的药物靶标。已通过 X 射线晶体学和低温 EM 建立了 NTS ₁结构景观的详细图片，然而，受体与 G 蛋白和抑制蛋白传感器偶联的分子决定因素仍未明确定义。我们使用¹³ C ^ε H ₃-甲硫氨酸 NMR 光谱显示磷脂酰肌醇-4,5-二磷酸 (PIP2) 促进换能器络合不是通过显着改变受体结构，而是通过加强远程变构连接，以相关构象动力学的形式，在正构口袋和高度之间-保守的激活基序。β-arrestin-1 通过减少共振子集的构象交换动力学进一步重塑受体集合，而 G 蛋白偶联对速率几乎没有影响。β-arrestin 偏向变构调节剂将 NTS1:G 蛋白复合物转化为子状态的串联，而不会触发传感器解离，这表明它可能通过稳定信号转导无能力的 G 蛋白构象（例如非规范状态）来发挥作用。一起，