清华大学刘翔宇小组研制了GPCR-G蛋白-β-抑制蛋白巨复合体由一种多功能变构调节剂激活。这一研究成果发表在2026年1月27日出版的国际学术期刊《细胞》上。

利用同源体内发展的生存压力选择（SPS）方法，一种发现GPCR激动剂的高通量平台，研究团队发现了一种变构配体，该配体稳定GPCR-G蛋白-β-抑制蛋白巨复合物，从而介导内化后的受体信号传导。值得注意的是，这种化合物atazanavir表现出跨多个家族A GPCR的泛受体激活，包括GPR119、β1AR和β2AR，表明了这种调节机制的广泛适用性。这一发现揭示了GPCR调控的独特机制，为开发靶向GPCR的治疗方法开辟了新的途径。

据了解，大约三分之一的临床药物通过G蛋白偶联受体（GPCR）介导其治疗效果，突出了其巨大的治疗相关性。调节GPCR活性的新方法有可能产生独特的药理学特征。传统上，GPCR下游的G蛋白和β-阻滞蛋白信号通路被认为是相互排斥的。

附：英文原文

Title: A GPCR-G protein-β-arrestin megacomplex enabled by a versatile allosteric modulator

Author: Guodong He, Qinxin Sun, Xinyu Xu, Fang Kong, Shuhao Zhang, Kexin Ye, Xiaoou Sun, Bin Lin, Xin Chen, Chuangye Yan, Xiangyu Liu

Issue&Volume: 2026-01-27

Abstract: Approximately one-third of clinical drugs mediate their therapeutic effects through G protein-coupled receptors (GPCRs), highlighting their immense therapeutic relevance. Novel approaches to modulate GPCR activity have the potential to yield unique pharmacological profiles. Conventionally, the G protein and β-arrestin signaling pathways downstream of GPCRs have been viewed as mutually exclusive. Using the in-house developed survival pressure selection (SPS) method, a high-throughput platform for GPCR agonist discovery, we identified an allosteric ligand that stabilizes a GPCR-G protein-β-arrestin megacomplex, thereby mediating sustained receptor signaling following internalization. Remarkably, this compound, atazanavir, exhibits pan-receptor activation across multiple family A GPCRs, including GPR119, β1AR, and β2AR, demonstrating the broad applicability of this regulatory mechanism. This discovery uncovers a distinct mechanism of GPCR regulation, opening alternative avenues for the development of therapeutics targeting GPCRs.

DOI: 10.1016/j.cell.2025.12.023

Source: https://www.cell.com/cell/abstract/S0092-8674(25)01436-9