β-抑制因子的小分子调控
β-抑制因子的小分子调控，这一成果由杜克大学Robert J. Lefkowitz小组经过不懈努力而取得。相关论文于2026年6月24日发表在《自然》杂志上。
在这里，小组报道了选择性靶向β-阻滞蛋白的小分子抑制剂的鉴定，并通过综合药理学、生化、生物物理和结构分析描述了它们的作用机制。这些抑制剂破坏β-阻滞蛋白与激动剂激活的GPCR的结合，损害脱敏、内化和β-阻滞蛋白依赖的生理功能，同时保留G蛋白-受体偶联。低温电子显微镜、分子动力学模拟和结构导向诱变表明，一种调制剂Cmpd-5与β-arrestin1中央波峰内的一个由中间环、C环和lariat环组成的小洞结合，这是一个关键的受体结合界面，稳定了一个与β-arrestin1受体完全结合不相容的独特构象。总之，这些发现建立了β-抑制蛋白调节的机制框架，揭示了基于结构的药物设计的新变构位点，并为传感器靶向，途径特异性GPCR治疗剂开辟了新的途径。
据介绍，β-Arrestins是g蛋白偶联受体（GPCR）信号传导的多功能调节剂，并在GPCR超家族中协调多种下游信号传导事件和生理反应。虽然GPCR药理学已经发展到靶向正构和变构位点，以及G蛋白和GPCR激酶，但直接调节β-阻滞蛋白活性的化学工具仍然明显缺乏。
附：英文原文
Title: Small-molecule modulation of β-arrestins
Author: Kahsai, Alem W., Pakharukova, Natalia, Kwon, Henry Y., Shah, Kunal S., del Real, Caroline T., Shreiber, Bowie N., Liang-Lin, Jason G., Shim, Paul J., Lee, Mason A., Ngo, Van A., Schwalb, Allison M., Pham, Uyen, Chundi, Anand, Jiang, Haoran, Flores-Espinoza, Emmanuel, Liu, Samuel, Nibley, Preston C., Bassford, Dana K., Hahn, Hyunggu, Kunzle, Cal A., Thomas, Brittany N., Kim, Jihee, Zhou, Yang, Wang, Jialu, Zhang, Xingdong, Smith, Jeffrey S., Rein, Lindsay A. M., Thomsen, Alex R. B., Shenoy, Sudha K., Rajagopal, Sudarshan, Shi, Lei, Ahn, Seungkirl, Rockman, Howard A., Masoudi, Ali, Lefkowitz, Robert J.
Issue&Volume: 2026-06-24
Abstract: β-Arrestins are multifunctional regulators of G-protein-coupled receptor (GPCR) signalling and orchestrate diverse downstream signalling events and physiological responses across the GPCR superfamily1,2,3. Although GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GPCR kinases, direct chemical tools to modulate β-arrestin activities have remained conspicuously absent. Here we report the identification of small-molecule inhibitors that selectively target β-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical and structural analyses. These inhibitors disrupt β-arrestin engagement with agonist-activated GPCRs, impairing desensitization, internalization and β-arrestin-dependent physiological functions while sparing G protein–receptor coupling. Cryo-electron microscopy, molecular dynamics simulations and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a pocket within the central crest of β-arrestin1 formed by the middle, C and lariat loops, a critical receptor-binding interface, stabilizing a distinct conformation that is incompatible with full β-arrestin–receptor engagement. Together, these findings establish a mechanistic framework for β-arrestin modulation, reveal a novel allosteric site for structure-based drug design, and open new avenues for transducer-targeted, pathway-specific GPCR therapeutic agents.
DOI: 10.1038/s41586-026-10683-5