Structure of the human glucagon class B G-protein-coupled receptor.
ABSTRACT Binding of the glucagon peptide to the glucagon receptor (GCGR) triggers the release of glucose from the liver during fasting; thus GCGR plays an important role in glucose homeostasis. Here we report the crystal structure of the seven transmembrane helical domain of human GCGR at 3.4 Å resolution, complemented by extensive site-specific mutagenesis, and a hybrid model of glucagon bound to GCGR to understand the molecular recognition of the receptor for its native ligand. Beyond the shared seven transmembrane fold, the GCGR transmembrane domain deviates from class A G-protein-coupled receptors with a large ligand-binding pocket and the first transmembrane helix having a 'stalk' region that extends three alpha-helical turns above the plane of the membrane. The stalk positions the extracellular domain (∼12 kilodaltons) relative to the membrane to form the glucagon-binding site that captures the peptide and facilitates the insertion of glucagon's amino terminus into the seven transmembrane domain.
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ABSTRACT: Oxyntomodulin (OXM) is a peptide hormone released from the gut in post-prandial state that activates both the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) resulting in superior body weight lowering to selective GLP1R agonists. OXM reduces food intake and increases energy expenditure in humans. While activation of the GCGR increases glucose production posing a hyperglycemic risk, the simultaneous activation of the GLP1R counteracts this effect. Acute OXM infusion improves glucose tolerance in T2DM patients making dual agonists of the GCGR and GLP1R new promising treatments for diabetes and obesity with the potential for weight loss and glucose lowering superior to that of GLP1R agonists.Molecular metabolism. 06/2014; 3(3):241-251.
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ABSTRACT: The past decade has witnessed an impressive expansion of our knowledge of retinal photoreceptor signal transduction and the regulation of the visual cycle required for normal eyesight. Progress in human genetics and next generation sequencing technologies have revealed the complexity behind many inherited retinal diseases. Structural studies have markedly increased our understanding of the visual process. Moreover, technical innovations and improved methodologies in proteomics, macromolecular crystallization and high resolution imaging at different levels set the scene for even greater advances. Pharmacology combined with structural biology of membrane proteins holds great promise for developing innovative accessible therapies for millions robbed of their sight or progressing toward blindness.Current opinion in cell biology 04/2014; 27C:32-43. · 14.15 Impact Factor
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ABSTRACT: The classic paradigm of G protein-coupled receptor (GPCR) activation was based on the understanding that agonist binding to a receptor induces or stabilizes a conformational change to an 'active' conformation. In the past decade, however, it has been appreciated that ligands can induce distinct 'active' receptor conformations with unique downstream functional signaling profiles. Building on the initial recognition of the existence of such 'biased ligands', recent years have witnessed significant developments in several areas of GPCR biology. These include increased understanding of structural and biophysical mechanisms underlying biased agonism, improvements in characterization and quantification of ligand efficacy, as well as clinical development of these novel ligands. Here we review recent major developments in these areas over the past several years.Current opinion in cell biology 04/2014; 27C:18-24. · 14.15 Impact Factor