NTSR1 G蛋白亚型混杂的动态基础快照，这一成果由贝勒医学院Michael J. Robertson小组经过不懈努力而取得。相关论文于2026年3月11日发表于国际顶尖学术期刊《自然》杂志上。

在这里，研究组使用时间分辨冷冻电子显微镜来观察GTP诱导的Gα_i1βγ和Gα₁₁βγ异源三聚体与神经紧张素受体1 （NTSR1）结合的激活，这些异源三聚体已被证明在G蛋白偶联中高度混杂，并且在无核苷酸复合物中具有非核构象。研究小组分析了G蛋白激活途径上的状态集合，分析了Gα_i1和Gα₁₁在结构和相对居群上的差异。结构分析揭示了几个基序，包括细胞内环2（ICL2）和ICL3，在稳定观察到的中间状态中起关键作用。

分子动力学模拟和动态生物发光共振能量转移实验支持了他们的研究结果，揭示了这些中间状态的稳定性和各种G蛋白的信号传导与ICL2和ICL3序列相关。GTP诱导的NTSR1–G蛋白复合物解离的单分子荧光分析显示，NTSR1从Gα₁₁中释放的速度明显快于Gα_i1，这与Gα₁₁-GTP中间状态相对缺乏一致。这些发现强调了沿G蛋白激活途径的瞬时中间态复合物在G蛋白选择中具有重要作用，这不能仅用无核苷酸状态来解释。

据介绍，G蛋白偶联受体（GPCRs）能够通过其G蛋白α亚基家族进行信号传导。尽管数百种无核苷酸的GPCR-G蛋白复合物结构已经被解决，但G蛋白亚型选择性的机制仍然知之甚少，最近的研究表明动态核苷酸结合中间态的作用。

附：英文原文

Title: Snapshots of the dynamic basis of NTSR1 G protein subtype promiscuity

Author: Vo, Alina A., Modak, Arnab, Lu, Sumin, Blanchard, Scott C., Lambert, Nevin A., Robertson, Michael J.

Issue&Volume: 2026-03-11

Abstract: G-protein-coupled receptors (GPCRs) are capable of signalling through four families of G protein α subunits. Although hundreds of nucleotide-free GPCR–G protein complex structures have been solved, the mechanism of G protein subtype selectivity remains poorly understood, with recent studies suggesting a role for dynamic nucleotide-bound intermediate states1,2. Here we use time-resolved cryo-electron microscopy to visualize the GTP-induced activation of Gαi1βγ and Gα11βγ heterotrimers bound to the neurotensin receptor 1 (NTSR1), which has been demonstrated to be highly promiscuous in G protein coupling and to possess unusual conformations in the nucleotide-free complex. We resolve ensembles of states along the G protein activation pathway, with differences in the structures and their relative populations between Gαi1 and Gα11. Structural analysis reveals a key role for several motifs, including intracellular loop 2 (ICL2) and ICL3, in stabilizing the observed intermediate states. Our results are supported by molecular dynamics simulations and kinetic bioluminescence resonance energy transfer experiments, which reveal that the stability of these intermediate states and the signalling of various G proteins are correlated with ICL2 and ICL3 sequences. Single-molecule fluorescence assays of GTP-induced NTSR1–G protein complex dissociation reveal that NTSR1 is liberated significantly faster from Gα11, consistent with the relative lack of stable Gα11-GTP intermediate states compared with Gαi1. These findings highlight that transient intermediate-state complexes along the G protein activation pathway have an important role in G protein selection that cannot be explained by nucleotide-free states alone.

DOI: 10.1038/s41586-026-10120-7

Source: https://www.nature.com/articles/s41586-026-10120-7