近日，德国莱比锡大学教授Andreas Bock及其研究组揭示了配体特异性激活轨迹决定了细胞中的GPCR信号传导。2026年1月14日出版的《自然》发表了这项成果。

在这里，小组将遗传密码扩展和生物正交标记作为主题，为典型的GPCR， M₂甲基乙酰胆碱受体（M₂R）生成一组基于荧光的生物传感器。这些生物传感器能够实时监测激动剂促进的受体在完整细胞的细胞外表面的构象变化。该团队证明了不同的激动剂产生至少一种不同的G蛋白结合M₂R活性状态的平衡，每种激动剂都具有不同的激活G蛋白的能力。这些M₂R- G蛋白复合物的形成发生在0.2-5秒沿着包括常见和配体特异性构象变化的轨迹，似乎决定了G蛋白的选择性。这些观察结果揭示了完整细胞中配体功效的分子性质。选择性地利用这种不同的GPCR激活轨迹和构象平衡可能为GPCR药物发现开辟新的途径。

据悉，G蛋白偶联受体（GPCRs）是细胞通讯的关键介质，代表了最重要的一类药物靶点。体外纯化GPCRs的生物物理研究表明，它们存在于不同的无活性和活性状态的平衡中，这种平衡是由配体以一种药效依赖的方式调节的。然而，功效是如何编码的以及活细胞中是否存在多种受体状态仍不清楚。

附：英文原文

Title: Ligand-specific activation trajectories dictate GPCR signalling in cells

Author: Thomas, Romy, Jacoby, Pauline S., De Faveri, Chiara, Derieux, Ccile, Liebing, Aenne-Dorothea, Melkes, Barbora, Martini, Hans-Joachim, Bermdez, Marcel, Stubert, Claudia, Lohse, Martin J., Coin, Irene, Bock, Andreas

Issue&Volume: 2026-01-14

Abstract: G-protein-coupled receptors (GPCRs) are key mediators of cell communication and represent the most important class of drug targets1,2. Biophysical studies with purified GPCRs in vitro have suggested that they exist in an equilibrium of distinct inactive and active states, which is modulated by ligands in an efficacy-dependent manner3,4,5,6,7,8,9,10,11. However, how efficacy is encoded and whether multiple receptor states occur in living cells remain unclear. Here we use genetic code expansion12 and bioorthogonal labelling13,14,15,16 to generate a panel of fluorescence-based biosensors for a prototypical GPCR, the M2 muscarinic acetylcholine receptor (M2R). These biosensors enable real-time monitoring of agonist-promoted conformational changes across the receptor’s extracellular surface in intact cells. We demonstrate that different agonists produce equilibria of at least four distinct active states of the G-protein-bound M2R, each with a different ability to activate G proteins. The formation of these M2R–G-protein complexes occurs over 0.2–5s along trajectories that involve both common and ligand-specific conformational changes and appear to determine G-protein selectivity. These observations reveal the molecular nature of ligand efficacy in intact cells. Selectively exploiting such different GPCR activation trajectories and conformational equilibria may open new avenues for GPCR drug discovery.

DOI: 10.1038/s41586-025-09963-3

Source: https://www.nature.com/articles/s41586-025-09963-3