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

Abstract

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.

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Fig. 1: Comparison between predicted models and experimental structures with large ECD.
Fig. 2: Evaluation for the orthosteric ligand-binding sites.
Fig. 3: Comparison of TMD conformations at extracellular side.
Fig. 4: Comparison of TM6 conformations at intracellular side.

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Acknowledgements

This work was partially supported by Lingang Laboratory grant (LG202102-01-01 to XC); Ministry of Science and Technology (China) grants (2018YFA0507002 to HEX); Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to HEX); Shanghai Municipal Science and Technology Major Project (HEX); CAS Strategic Priority Research Program (XDB37030103 to HEX); the National Natural Science Foundation of China (32130022 to HEX, 32171187 to YJ, 82121005 to HEX and YJ); and Shanghai Municipal Science and Technology Major Project.

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Correspondence to Yi Jiang, H. Eric Xu or Xi Cheng.

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He, Xh., You, Cz., Jiang, Hl. et al. AlphaFold2 versus experimental structures: evaluation on G protein-coupled receptors. Acta Pharmacol Sin (2022). https://doi.org/10.1038/s41401-022-00938-y

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Keywords

  • G protein-coupled receptors
  • AlphaFold2
  • protein structure prediction
  • drug design
  • structural biology

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