van der Velden Wijnand J C, Mukhaleva Elizaveta, Vaidehi Nagarajan
Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, California, USA.
Department of Computational and Quantitative Medicine, Beckman Research Institute of the City of Hope, Duarte, California, USA.
J Biol Chem. 2025 Apr 23;301(6):108530. doi: 10.1016/j.jbc.2025.108530.
Recent drug development suggests agonists may be more promising against glucagon receptor dysregulation in metabolic disorders. Allosteric modulation may pave an alternative way to initiate responses that are required to target these metabolic disorders. Here, we investigated the allosteric communication mechanisms within the glucagon receptor using molecular dynamics simulations on five receptor states. Results highlighted that the extracellular domain is dynamic in the absence of an orthosteric agonist. In the presence of a partial agonist, we observed increased flexibility in the N terminus of the receptor compared with the full agonist-bound receptor. Class B1 G protein-coupled receptor (GPCR) microswitches showed repacking going from the inactive state to the active state, allowing for G protein coupling. In the full agonist- and G protein-bound state, Gα showed both translational and rotational movement in the N terminus, core, and α5-helix, thereby forming key interactions between the core of the G protein and the receptor. Finally, the allosteric communication from the extracellular region to the G protein coupling region of the receptor was the strongest in the intracellular negative allosteric modulator-bound state, the full agonist and G protein-bound state, and the full agonist-bound G protein-free state. The residue positions predicted to play a significant role in the allosteric communication mechanism showed overlap with disease-associated mutations. Overall, our study provides insights into the allosteric communication mechanism in a class B1 GPCR, which sets the foundation for future design of allosteric modulators targeting the glucagon receptor.
近期的药物研发表明，激动剂在对抗代谢紊乱中的胰高血糖素受体失调方面可能更具前景。变构调节可能为引发针对这些代谢紊乱所需的反应开辟一条替代途径。在此，我们通过对五种受体状态进行分子动力学模拟，研究了胰高血糖素受体内的变构通讯机制。结果表明，在没有正构激动剂的情况下，细胞外结构域是动态的。在存在部分激动剂的情况下，我们观察到与完全激动剂结合的受体相比，该受体的N端灵活性增加。B1类G蛋白偶联受体（GPCR）微开关显示从非活性状态到活性状态的重新排列，从而实现G蛋白偶联。在完全激动剂和G蛋白结合状态下，Gα在N端、核心和α5螺旋中均表现出平移和旋转运动，从而在G蛋白核心与受体之间形成关键相互作用。最后，从细胞外区域到受体的G蛋白偶联区域的变构通讯在细胞内负变构调节剂结合状态、完全激动剂和G蛋白结合状态以及完全激动剂结合的无G蛋白状态下最强。预测在变构通讯机制中起重要作用的残基位置与疾病相关突变存在重叠。总体而言，我们的研究为B1类GPCR中的变构通讯机制提供了见解，为未来设计靶向胰高血糖素受体的变构调节剂奠定了基础。
