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Structural biology

Full monty of family B GPCRs

Nature Chemical Biology volume 13, pages 819–821 (2017)Cite this article

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New structures of the glucagon-like peptide-1 (GLP-1) and glucagon receptors in complex with peptide and nonpeptide ligands provide a comprehensive, detailed picture of the molecular mechanisms of action of family B GPCRs. This opens the door for true structure-based drug discovery aimed at both novel orthosteric and allosteric subsites of the receptors.

G-protein-coupled receptors (GPCRs) constitute the largest family of cell-surface receptors, transducing extracellular chemical signals into intracellular signals. The structure and function of the nominally largest subfamily of these, the rhodopsin-like or family A receptor family, have been characterized in great detail, as reflected by more than 140 published X-ray structures. By contrast, family B receptors, which are activated by a series of important peptide hormones and neuropeptides and share only the overall secondary and tertiary structure of the seven-helical bundle with family A receptors, have been much more resistant to structural analysis. Now, a near-atomic resolution structure of the family B GLP-1 receptor, the target for blockbuster type 2 diabetes and obesity peptide-based drugs, has been solved by cryo-EM. Importantly, it is a structure of the active conformation of an unmodified, full-length GLP-1 receptor in complex with both the natural peptide ligand and the heterotrimeric G protein Gs, which conveys intracellular signaling1. This landmark structure was published along with three X-ray crystallography papers describing the following findings: the binding of a truncated GLP-1 peptide mimetic to the full-length GLP-1 receptor2; the binding of nonpeptide allosteric modulators to the outside of the transmembrane domain of the GLP-1 receptor3; and an inactive conformation of the full-length glucagon receptor (another family B receptor) in complex with a similar nonpeptide allosteric modulator4. Together, these papers provide a broad, almost comprehensive picture of both physiological and pharmacological mechanisms in family B GPCR activation and inactivation.

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Figure 1: Ligand binding and activation of a family B GPCR and the GLP-1 receptor.

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  1. Department of Biomedical Research at University of Copenhagen, Section for Metabolic Receptology at the Center for Basic Metabolic Research and Laboratory for Molecular Pharmacology

    Thue W Schwartz

  2. Section for Metabolic Receptology at the Center for Basic Metabolic Research at University of Copenhagen

    Thomas M Frimurer

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  1. Thue W Schwartz
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  2. Thomas M Frimurer
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Correspondence to Thue W Schwartz or Thomas M Frimurer.

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Schwartz, T., Frimurer, T. Full monty of family B GPCRs. Nat Chem Biol 13, 819–821 (2017). https://doi.org/10.1038/nchembio.2438

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