Abstract
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, with many GPCRs having crucial roles in endocrinology and metabolism. Cryogenic electron microscopy (cryo-EM) has revolutionized the field of structural biology, particularly regarding GPCRs, over the past decade. Since the first pair of GPCR structures resolved by cryo-EM were published in 2017, the number of GPCR structures resolved by cryo-EM has surpassed the number resolved by X-ray crystallography by 30%, reaching >650, and the number has doubled every ~0.63 years for the past 6 years. At this pace, it is predicted that the structure of 90% of all human GPCRs will be completed within the next 5–7 years. This Review highlights the general structural features and principles that guide GPCR ligand recognition, receptor activation, G protein coupling, arrestin recruitment and regulation by GPCR kinases. The Review also highlights the diversity of GPCR allosteric binding sites and how allosteric ligands could dictate biased signalling that is selective for a G protein pathway or an arrestin pathway. Finally, the authors use the examples of glycoprotein hormone receptors and glucagon-like peptide 1 receptor to illustrate the effect of cryo-EM on understanding GPCR biology in endocrinology and metabolism, as well as on GPCR-related endocrine diseases and drug discovery.
Key points
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Cryogenic electron microscopy (cryo-EM) has revolutionized G protein-coupled receptor (GPCR) drug discovery, providing detailed insights into GPCR structures, allosteric modulation and biased signalling, and advancing precision medicine for metabolic disorders.
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Biased ligands enable precise modulation of GPCR signalling, offering the possibility of tailored therapeutic strategies in the discovery of drugs for endocrine and metabolic diseases.
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Ligand binding to GPCRs induces key structural changes, activating GPCRs for signal transduction via G proteins and arrestins, as determined by transmembrane helix 6 movement and phosphorylation states.
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GPCRs are modulated by diverse allosteric ligands at various sites, offering insights into drug development and therapeutic strategies.
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GPCRs have a pivotal role in endocrine diseases and metabolic conditions, making them promising therapeutic targets; cryo-EM has provided a better understanding of GPCRs that will enhance the development of precision drugs.
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Acknowledgements
The authors acknowledge the support of the CAS Strategic Priority Research Program (XDB37030103 to H.E.X.); Shanghai Municipal Science and Technology Major Project (2019SHZDZX02 to H.E.X.); Shanghai Municipal Science and Technology Major Project (H.E.X.); The National Natural Science Foundation of China (32130022 and 82121005 to H.E.X.); the Lingang Laboratory (grant no. LG-GG-202204-01 to H.E.X.); and the National Key R&D Program of China (2022YFC2703105 to H.E.X.); The National Natural Science Foundation of China (82373881 to J.D.); Young Elite Scientists Sponsorship Program by CAST (2022QNRC001 to J.D.); Shanghai Sailing Program (23YF1456800 to J.D.); and the Youth Innovation Promotion Association of Chinese Academy of Sciences (to J.D.).
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H.E.X. is the founder and stakeholder of Cascade Pharmaceuticals. The other authors declare no competing interests.
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Duan, J., He, XH., Li, SJ. et al. Cryo-electron microscopy for GPCR research and drug discovery in endocrinology and metabolism. Nat Rev Endocrinol (2024). https://doi.org/10.1038/s41574-024-00957-1
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DOI: https://doi.org/10.1038/s41574-024-00957-1
