As important drug targets, G protein-coupled receptors (GPCRs) play pivotal roles in a wide range of physiological processes. Extensive efforts of structural biology have been made on the study of GPCRs. However, a large portion of GPCR structures remain unsolved due to structural instability. Recently, AlphaFold2 has been developed to predict structure models of many functionally important proteins including all members of the GPCR family. Herein we evaluated the accuracy of GPCR structure models predicted by AlphaFold2. We revealed that AlphaFold2 could capture the overall backbone features of the receptors. However, the predicted models and experimental structures were different in many aspects including the assembly of the extracellular and transmembrane domains, the shape of the ligand-binding pockets, and the conformation of the transducer-binding interfaces. These differences impeded the use of predicted structure models in the functional study and structure-based drug design of GPCRs, which required reliable high-resolution structural information.

作为重要的药物靶点，G蛋白偶联受体（GPCR）在广泛的生理过程中发挥着关键作用。结构生物学在GPCR的研究上做出了广泛的努力。然而，由于结构不稳定，很大一部分 GPCR 结构仍未得到解决。最近，AlphaFold2 已被开发用于预测许多功能重要的蛋白质（包括 GPCR 家族的所有成员）的结构模型。在此，我们评估了 AlphaFold2 预测的 GPCR 结构模型的准确性。我们发现 AlphaFold2 可以捕获受体的整体主干特征。然而，预测的模型和实验结构在许多方面都不同，包括细胞外和跨膜结构域的组装、配体结合袋的形状以及传感器结合界面的构象。这些差异阻碍了预测结构模型在 GPCR 的功能研究和基于结构的药物设计中的使用，而这需要可靠的高分辨率结构信息。