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Structure of the glucagon receptor in complex with a glucagon analogue.

Zhang H, Qiao A, Yang L, Van Eps N, Frederiksen KS, Yang D, Dai A, Cai X, Zhang H, Yi C, Cao C, He L, Yang H, Lau J, Ernst OP, Hanson MA, Stevens RC, Wang MW, Reedtz-Runge S, Jiang H, Zhao Q, Wu B
Nature 553 106-110 (2018)
Cited: 75 times
EuropePMC logo PMID: 29300013

Abstract

Class B G-protein-coupled receptors (GPCRs), which consist of an extracellular domain (ECD) and a transmembrane domain (TMD), respond to secretin peptides to play a key part in hormonal homeostasis, and are important therapeutic targets for a variety of diseases. Previous work has suggested that peptide ligands bind to class B GPCRs according to a two-domain binding model, in which the C-terminal region of the peptide targets the ECD and the N-terminal region of the peptide binds to the TMD binding pocket. Recently, three structures of class B GPCRs in complex with peptide ligands have been solved. These structures provide essential insights into peptide ligand recognition by class B GPCRs. However, owing to resolution limitations, the specific molecular interactions for peptide binding to class B GPCRs remain ambiguous. Moreover, these previously solved structures have different ECD conformations relative to the TMD, which introduces questions regarding inter-domain conformational flexibility and the changes required for receptor activation. Here we report the 3.0 Å-resolution crystal structure of the full-length human glucagon receptor (GCGR) in complex with a glucagon analogue and partial agonist, NNC1702. This structure provides molecular details of the interactions between GCGR and the peptide ligand. It reveals a marked change in the relative orientation between the ECD and TMD of GCGR compared to the previously solved structure of the inactive GCGR-NNC0640-mAb1 complex. Notably, the stalk region and the first extracellular loop undergo major conformational changes in secondary structure during peptide binding, forming key interactions with the peptide. We further propose a dual-binding-site trigger model for GCGR activation-which requires conformational changes of the stalk, first extracellular loop and TMD-that extends our understanding of the previously established two-domain peptide-binding model of class B GPCRs.

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  1. G protein-coupled receptors: structure- and function-based drug discovery. Yang D, Zhou Q, Labroska V, Qin S, Darbalaei S, Wu Y, Yuliantie E, Xie L, Tao H, Cheng J, Liu Q, Zhao S, Shui W, Jiang Y, Wang MW. Signal Transduct Target Ther 6 7 (2021)
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  3. Structural basis of GPCR coupling to distinct signal transducers: implications for biased signaling. Seyedabadi M, Gharghabi M, Gurevich EV, Gurevich VV. Trends Biochem Sci 47 570-581 (2022)
  4. Engineering of Challenging G Protein-Coupled Receptors for Structure Determination and Biophysical Studies. Waltenspühl Y, Ehrenmann J, Klenk C, Plückthun A. Molecules 26 1465 (2021)

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  1. Mechanisms of signalling and biased agonism in G protein-coupled receptors. Wootten D, Christopoulos A, Marti-Solano M, Babu MM, Sexton PM. Nat Rev Mol Cell Biol 19 638-653 (2018)
  2. The Discovery and Development of Liraglutide and Semaglutide. Knudsen LB, Lau J. Front Endocrinol (Lausanne) 10 155 (2019)
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  5. RAMPs as allosteric modulators of the calcitonin and calcitonin-like class B G protein-coupled receptors. Pioszak AA, Hay DL. Adv Pharmacol 88 115-141 (2020)
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  8. Structural Basis for Allosteric Modulation of Class B G Protein-Coupled Receptors. Wootten D, Miller LJ. Annu Rev Pharmacol Toxicol 60 89-107 (2020)
  9. Capturing Peptide-GPCR Interactions and Their Dynamics. Kaiser A, Coin I. Molecules 25 E4724 (2020)
  10. PAC1 Receptors: Shapeshifters in Motion. Liao C, May V, Li J. J Mol Neurosci 68 331-339 (2019)
  11. Metabolic Effects of Metformin in Humans. Adeva-Andany MM, Rañal-Muíño E, Fernández-Fernández C, Pazos-García C, Vila-Altesor M. Curr Diabetes Rev 15 328-339 (2019)
  12. Glucagon and Its Receptors in the Mammalian Heart. Neumann J, Hofmann B, Dhein S, Gergs U. Int J Mol Sci 24 12829 (2023)
  13. Exploring GPCR conformational dynamics using single-molecule fluorescence. Agyemang E, Gonneville AN, Tiruvadi-Krishnan S, Lamichhane R. Methods 226 35-48 (2024)
  14. Insights into the structure and activation mechanism of some class B1 GPCR family members. Aksu H, Demirbilek A, Uba AI. Mol Biol Rep 51 966 (2024)

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