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3.0 A-resolution crystal structure of the full-length human glucagon receptor (GCGR) in complex with a glucagon analogue and partial agonist, NNC1702
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work toward the mapping of interactions between the polypeptide hormone glucagon and the glucagon receptor
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3.0 A crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation
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This work suggests that RAMP2 may modify the agonist activity and trafficking of the GCGR, with potential relevance to production of new peptide analogs with selective agonist activities.
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Data suggest that GCGR activation proceeds via a mechanism in which transmembrane helix 6 (TM6) is held in an inactive conformation by a conserved polar core and a hydrophobic lock (involving intracellular loop 3, IC3); mutations in the corresponding polar core of GCGR disrupt these inhibitory elements, allow TM6 to swing outward, and induce constitutive G protein signaling.
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The activation of the GCGR is characterized by the outward movement of the intracellular side of helix VI. In the active state of the GCGR, the Arg173(2.46)-Ser350(6.41) and Glu245(3.50)-Thr351(6.42) hydrogen bonds break, and the chi1 rotamer of Phe322(5.54) changes from perpendicular to parallel to helix VI.
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In the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the extracellular domain is required for signaling even when the hormone is covalently linked to the transmembrane domain.
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2.5 A crystal structure of human GCGR in complex with the antagonist MK-0893, which is found to bind to an allosteric site outside the seven transmembrane helical bundle in a position between TM6 and TM7 extending into the lipid bilayer
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Molecular dynamics and disulfide crosslinking studies suggest that apo-GCGR can adopt both an open and closed conformation associated with extensive contacts between the ECD and 7TM domain. Glucagon binds to GCGR by a conformational selection mechanism.
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glucagon cell adenomatosis with GCGR germline mutations seems to follow an autosomal-recessive trait.
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Using a real-time time-resolved FRET-based internalization assay, we show that GLP-1R, GIPR, and GCGR internalize with differential properties
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crystal structure of the seven transmembrane helical domain of human GCGR at 3.4 A resolution, and a hybrid model of glucagon bound to GCGR to understand the molecular recognition of the receptor for its native ligand
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Letter/Case Report: nonfunctional glucagon cell adenomatosis with no detectable glucagon receptor mutations.
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GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism
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F22, V23, M27, and D15 of GCGR are the most important residues for glucagon binding.
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in addition to activation of the classic cAMP/protein kinase A (PKA) pathway, activation of GCGR also induced beta-catenin stabilization and activated beta-catenin-mediated transcription
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analysis of glucagon receptor antagonists with reduced molecular weight and lipophilicity
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The P86S mutant GCGR shows abnormal receptor internalization & calcium mobilization, & causes apoptosis. It cases Mahvash disease (hyperglucagonemia, hypoglycemia, pancreatic neuroendocrine tumors).
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substituted cysteine accessibility method and 3D-molecular modeling to study the N-terminal domain; results showed that Asp(63), Arg(116), and Lys(98) are essential for the receptor structure and/or ligand binding
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The [Ca2+] response is induced by glucagon mainly via the coupling of GCGR to the Galphaq/11 and Galphai/o proteins.
