Review Article

AlphaFold2 versus experimental structures: evaluation on G protein-coupled receptors

Xin-heng He1,2, Chong-zhao You1,2, Hua-liang Jiang1,2,3,4, Yi Jiang2,4, H. Eric Xu1,2, Xi Cheng1,2,3
1 State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China
4 Lingang Laboratory, Shanghai 200031, China
Correspondence to: Yi Jiang:, H. Eric Xu:, Xi Cheng:,
DOI: 10.1038/s41401-022-00938-y
Received: 11 March 2022
Accepted: 6 June 2022
Advance online: 1 July 2022


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.
Keywords: G protein-coupled receptors; AlphaFold2; protein structure prediction; drug design; structural biology

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