Oliveira de Souza, C., Sun, X. & Oh, D. Metabolic functions of G protein-coupled receptors and β-arrestin-mediated signaling pathways in the pathophysiology of type 2 diabetes and obesity. Front. Endocrinol. 12, 715877 (2021).

Article  Google Scholar 

Bockaert, J. & Pin, J. P. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J. 18, 1723–1729 (1999).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Garcia-Nafria, J. & Tate, C. G. Structure determination of GPCRs: cryo-EM compared with X-ray crystallography. Biochem. Soc. Trans. 49, 2345–2355 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Liang, Y. L. et al. Phase-plate cryo-EM structure of a class B GPCR-G-protein complex. Nature 546, 118–123 (2017).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Zhang, Y. et al. Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546, 248–253 (2017).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Yang, D. et al. G protein-coupled receptors: structure- and function-based drug discovery. Signal. Transduct. Target. Ther. 6, 7 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cheng, Z. et al. Luciferase reporter assay system for deciphering GPCR pathways. Curr. Chem. Genomics 4, 84–91 (2010).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Tomas, A., Jones, B. & Leech, C. New insights into beta-cell GLP-1 receptor and cAMP signaling. J. Mol. Biol. 432, 1347–1366 (2020).

Article  CAS  PubMed  Google Scholar 

Feng, X. T. et al. GPR40: a therapeutic target for mediating insulin secretion (review). Int. J. Mol. Med. 30, 1261–1266 (2012).

Article  CAS  PubMed  Google Scholar 

Bologna, Z. et al. Protein-coupled receptor signaling: new player in modulating physiology and pathology. Biomol. Ther. 25, 12–25 (2017).

Article  Google Scholar 

Gurevich, V. V. & Gurevich, E. V. Structural determinants of arrestin functions. Prog. Mol. Biol. Transl. Sci. 118, 57–92 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kang, D. S., Tian, X. & Benovic, J. L. Role of β-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking. Curr. Opin. Cell Biol. 27, 63–71 (2014).

Article  PubMed  Google Scholar 

Schoneberg, T. & Liebscher, I. Mutations in G protein-coupled receptors: mechanisms, pathophysiology and potential therapeutic approaches. Pharmacol. Rev. 73, 89–119 (2021).

Article  PubMed  Google Scholar 

Pitcher, J. A., Freedman, N. J. & Lefkowitz, R. J. G protein-coupled receptor kinases. Annu. Rev. Biochem. 67, 653–692 (1998).

Article  CAS  PubMed  Google Scholar 

Gurevich, V. V. & Gurevich, E. V. GPCR signaling regulation: the role of GRKs and arrestins. Front. Pharmacol. 10, 125 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Shukla, A. K., Xiao, K. & Lefkowitz, R. J. Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling. Trends Biochem. Sci. 36, 457–469 (2011).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hodavance, S. Y., Gareri, C., Torok, R. D. & Rockman, H. A. G protein-coupled receptor biased agonism. J. Cardiovasc. Pharmacol. 67, 193–202 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rankovic, Z., Brust, T. F. & Bohn, L. M. Biased agonism: an emerging paradigm in GPCR drug discovery. Bioorg. Med. Chem. Lett. 26, 241–250 (2016).

Article  CAS  PubMed  Google Scholar 

Violin, J. D., Crombie, A. L., Soergel, D. G. & Lark, M. W. Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol. Sci. 35, 308–316 (2014).

Article  CAS  PubMed  Google Scholar 

Bermudez, M., Nguyen, T. N., Omieczynski, C. & Wolber, G. Strategies for the discovery of biased GPCR ligands. Drug. Discov. Today 24, 1031–1037 (2019).

Article  CAS  PubMed  Google Scholar 

Laeremans, T. et al. Accelerating GPCR drug discovery with conformation-stabilizing VHHs. Front. Mol. Biosci. 9, 863099 (2022).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kawai, T. et al. Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. Proc. Natl Acad. Sci. USA 117, 29959–29967 (2020).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Jones, B. et al. Targeting GLP-1 receptor trafficking to improve agonist efficacy. Nat. Commun. 9, 1602 (2018).

Article  ADS  PubMed  PubMed Central  Google Scholar 

Coskun, T. et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 34, 1234–1247.e9 (2022).

Article  CAS  PubMed  Google Scholar 

Willard, F. S. et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight 5, e140532 (2020).

Article  PubMed  PubMed Central  Google Scholar 

Palczewski, K. et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739–745 (2000).

Article  ADS  CAS  PubMed  Google Scholar 

Cherezov, V. et al. High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor. Science 318, 1258–1265 (2007).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Rasmussen, S. G. et al. Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature 477, 549–555 (2011).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Rasmussen, S. G. et al. Crystal structure of the human β2 adrenergic G-protein-coupled receptor. Nature 450, 383–387 (2007).

Article  ADS  CAS  PubMed  Google Scholar 

Zhang, X. et al. Near-atomic resolution using electron cryomicroscopy and single-particle reconstruction. Proc. Natl Acad. Sci. USA 105, 1867–1872 (2008).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Liu, Y., Gonen, S., Gonen, T. & Yeates, T. O. Near-atomic cryo-EM imaging of a small protein displayed on a designed scaffolding system. Proc. Natl Acad. Sci. USA 115, 3362–3367 (2018).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Robertson, M. J. et al. Structure determination of inactive-state GPCRs with a universal nanobody. Nat. Struct. Mol. Biol. 29, 1188–1195 (2022).

Article  CAS  PubMed  Google Scholar 

Josephs, T. M. et al. Structure and dynamics of the CGRP receptor in apo and peptide-bound forms. Science 372, eabf7258 (2021).

Article  CAS  PubMed  Google Scholar 

Cong, Z. et al. Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor. Nat. Commun. 12, 3763 (2021).

Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Zhang, X. et al. Evolving cryo-EM structural approaches for GPCR drug discovery. Structure 29, 963–974.e6 (2021).

Article  CAS  PubMed