The glucagon-like peptide-1 receptor (GLP-1R) is a well-established drug target for the treatment of type II diabetes. The development of small-molecule positive allosteric modulators (PAMs) of GLP-1R is a promising therapeutic strategy. Here, we report the discovery and characterization of PAMs with distinct chemotypes, binding to a cryptic pocket formed by the cytoplasmic half of TM3, TM5, and TM6. Molecular dynamic simulations and mutagenesis studies indicate that the PAM enlarges the orthosteric pocket to facilitate GLP-1 binding. Further signaling assays characterized their probe-dependent signaling profiles. Our findings provide mechanistic insights into fine-tuning GLP-1R via this allosteric pocket and open up new avenues to design small-molecule drugs for class B G-protein-coupled receptors.

中文翻译：

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变构调节剂通过跨膜位点增强 GLP-1 与 GLP-1R 的结合

胰高血糖素样肽-1受体（GLP-1R）是治疗II型糖尿病的公认药物靶点。开发 GLP-1R 的小分子正变构调节剂 (PAM) 是一种很有前景的治疗策略。在这里，我们报告了具有不同化学型的 PAM 的发现和表征，它们与由 TM3、TM5 和 TM6 的细胞质一半形成的神秘口袋结合。分子动力学模拟和诱变研究表明，PAM 扩大了正构口袋以促进 GLP-1 结合。进一步的信号测定表征了它们的探针依赖性信号谱。我们的研究结果提供了通过这个变构口袋微调 GLP-1R 的机制见解，并开辟了为 B 类 G 蛋白偶联受体设计小分子药物的新途径。