Glucagon-like peptide-1 receptor (GLP-1R), as a member of the class B G protein-coupled receptors (GPCRs), plays a crucial role in regulating blood glucose level signal recognition through its activation. The conformation changes during the activation pathway are of particular importance for its function. To investigate the activation mechanism of GLP-1R, the crystal structures of active and inactive forms are chosen to perform a total of 2 μs of accelerated molecular dynamics (aMD) simulations and 400 ns of conventional molecular dynamics (cMD) simulations. With the aid of structural analysis and potential of mean force (PMF) calculations, we reveal the role of different helices in the activation and deactivation process and obtain the intermediate states during activation and deactivation that are difficult to capture in experiments. Protein structure network (PSN) was utilised to clarify the allosteric communication pathways of activation and deactivation and reveal the mechanisms of its activation and deactivation. The results could advance our understanding of the activation mechanism of GLP-1R and the related drug design.

胰高血糖素样肽1受体（GLP-1R）作为BG类蛋白偶联受体（GPCR）的成员，在通过激活其调节血糖水平信号识别中起着至关重要的作用。激活途径中的构象变化对其功能特别重要。为了研究GLP-1R的激活机制，选择了有活性和无活性形式的晶体结构，以执行总共2μs的加速分子动力学（aMD）模拟和400 ns的常规分子动力学（cMD）模拟。借助结构分析和潜在平均力（PMF）计算，我们揭示了不同螺旋在激活和失活过程中的作用，并获得了在激活和失活过程中很难在实验中捕获的中间状态。蛋白结构网络（PSN）用于阐明激活和失活的变构通讯途径，并揭示其激活和失活的机制。该结果可增进我们对GLP-1R激活机制及相关药物设计的了解。