Different domains of the glucagon and glucagon‐like peptide‐1 receptors provide the critical determinants of ligand selectivity

Runge, Steffen; Wulff, Birgitte S.; Madsen, Kjeld; Bräuner‐Osborne, Hans; Knudsen, Lotte Bjerre

doi:10.1038/sj.bjp.0705120

Cited by 109 publications

(133 citation statements)

References 52 publications

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“…The importance of the extracellular loop domains in ligand binding has been consistent for other members in the class B G protein-coupled receptor family, including receptors for secretin (14,15), vasoactive intestinal polypeptide (42,43), parathyroid hormone (44 -46), glucagon (47,48), growth hormone-releasing hormone (49), corticotropin-releasing factor (50), luteinizing hormone/choriogonadotropin (51-54), follicle-stimulating hormone (55)(56)(57), and gonadotropin-releasing hormone (58). In particular, the third extracellular loop has been shown to be important for high affinity binding for the parathyroid receptor (44,46).…”

Section: Resultsmentioning

confidence: 68%

Molecular Approximation between a Residue in the Amino-terminal Region of Calcitonin and the Third Extracellular Loop of the Class B G Protein-coupled Calcitonin Receptor

Dong

Pinon

Cox

et al. 2004

Journal of Biological Chemistry

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The calcitonin receptor is a member of the class B family of G protein-coupled receptors, which contains numerous potentially important drug targets. Delineation of themes for agonist binding and activation of these receptors will facilitate the rational design of receptor-active drugs. We reported previously that a photolabile residue within the carboxyl-terminal half (resi- Calcitonin (CT), 1 secreted by the thyroid gland in response to elevations in blood calcium levels, is a peptide hormone that regulates calcium by inhibition of osteoclast-mediated bone resorption (1, 2). CT acts on bone and kidney to maintain calcium homeostasis and is also present in the central nervous system, where it has anorectic and analgesic effects (3). It has been used therapeutically for the treatment of Paget's disease, the hypercalcemia associated with certain types of tumors, and osteoporosis (1, 2).dueCT is a relatively large peptide that contains 32 amino acids and has a diffuse pharmacophoric domain. Although residues throughout the entire length have been demonstrated to be critical for its biological activity, the amino-terminal residues of CT contain key determinants for its receptor agonist selectivity (1, 2). Truncation of the first seven amino-terminal residues that includes a disulfide bond between residues 1 and 7 results in antagonist action (4, 5). Residues 8 through 22 tend to form an amphiphilic ␣-helical structure that is important for high affinity binding (1).CT exhibits its agonist activities through binding to the CT receptor, a member of the class B family of guanine nucleotidebinding protein (G protein)-coupled receptors that have the seven-transmembrane-domain structure. Although they have topology similar to that of class A receptors, members of class B family share less than 12% amino acid identity with the more extensively studied receptors in the class A family. Class B receptors have distinct signature sequences, including a long complex amino-terminal domain with six conserved cysteine residues that are believed to be involved in intradomain disulfide bonds critical for establishing functional receptor conformation (6 -10). Members included in this family are receptors for moderately large peptides having diffuse pharmacophoric domains, such as secretin, calcitonin, glucagon, vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide, and parathyroid hormone, sharing 30 to 50% homology with each other.The unique amino-terminal domain of the CT receptor has been shown to be critical for agonist binding and receptor activation using chimeric receptor studies (11)(12)(13). This represents a consistent theme for other class B family members (14 -19). Photoaffinity labeling is a more direct approach for exploration of spatial approximations between residues within a ligand and within its receptor. Using this approach, we have recently demonstrated that probes incorporated a photolabile p-benzoyl-L-phenylalanine (Bpa) residue in the carboxyl-terminal half and mid-region of the ...

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Section: Resultsmentioning

confidence: 68%

Molecular Approximation between a Residue in the Amino-terminal Region of Calcitonin and the Third Extracellular Loop of the Class B G Protein-coupled Calcitonin Receptor

Dong

Pinon

Cox

et al. 2004

Journal of Biological Chemistry

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“…S3 B and C), suggesting that the ECD was "decoupled" from the JM region in the ECL3 chimeric receptor. Further evidence for this was provided by studies with a chimeric peptide that can bypass the ECD (12). Similar to glucagon, the activity of this ligand was significantly greater on the ECL3 chimeric receptor (Fig.…”

Section: Antagonist and Inverse Agonist Antibodies Targeting The Gcgrmentioning

confidence: 85%

“…Several GCGR antagonists that improve glycemic control in animal models of diabetes and diabetic patients have been described (3)(4)(5)(6)(7)(8). Although biochemical studies of glucagon and GCGR mutants have facilitated the mapping of some elements that contribute to glucagon binding (4,(9)(10)(11)(12), the molecular mechanisms of GCGR activation and inhibition remain largely unknown because there are currently no high-resolution structures of GCGR. The current model for activation class B GPCRs proposes a tethering mechanism whereby the C-terminal half of the peptide ligand first binds a large extracellular domain (ECD), thereby enabling a high-affinity interaction of the N-terminal half of the ligand with a cleft formed by the transmembrane α-helical bundle (13,14), termed the juxtamembrane (JM) domain.…”

mentioning

confidence: 99%

Molecular basis for negative regulation of the glucagon receptor

Koth¹,

Murray²,

Mukund³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

123

179

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Members of the class B family of G protein-coupled receptors (GPCRs) bind peptide hormones and have causal roles in many diseases, ranging from diabetes and osteoporosis to anxiety. Although peptide, small-molecule, and antibody inhibitors of these GPCRs have been identified, structure-based descriptions of receptor antagonism are scarce. Here we report the mechanisms of glucagon receptor inhibition by blocking antibodies targeting the receptor's extracellular domain (ECD). These studies uncovered a role for the ECD as an intrinsic negative regulator of receptor activity. The crystal structure of the ECD in complex with the Fab fragment of one antibody, mAb1, reveals that this antibody inhibits glucagon receptor by occluding a surface extending across the entire hormone-binding cleft. A second antibody, mAb23, blocks glucagon binding and inhibits basal receptor activity, indicating that it is an inverse agonist and that the ECD can negatively regulate receptor activity independent of ligand binding. Biochemical analyses of receptor mutants in the context of a high-resolution ECD structure show that this previously unrecognized inhibitory activity of the ECD involves an interaction with the third extracellular loop of the receptor and suggest that glucagon-mediated structural changes in the ECD accompany receptor activation. These studies have implications for the design of drugs to treat class B GPCR-related diseases, including the potential for developing novel allosteric regulators that target the ECDs of these receptors.T he glucagon receptor (GCGR) is a member of the class B G protein-coupled receptor (GPCR) family (1) that mediates the activity of glucagon, a pancreatic islet-derived peptide hormone that plays a central role in the pathophysiology of diabetes (2). Several GCGR antagonists that improve glycemic control in animal models of diabetes and diabetic patients have been described (3-8). Although biochemical studies of glucagon and GCGR mutants have facilitated the mapping of some elements that contribute to glucagon binding (4, 9-12), the molecular mechanisms of GCGR activation and inhibition remain largely unknown because there are currently no high-resolution structures of GCGR. The current model for activation class B GPCRs proposes a tethering mechanism whereby the C-terminal half of the peptide ligand first binds a large extracellular domain (ECD), thereby enabling a high-affinity interaction of the N-terminal half of the ligand with a cleft formed by the transmembrane α-helical bundle (13,14), termed the juxtamembrane (JM) domain. This interaction induces a structural change in the transmembrane and intracellular face of the receptor that enables G protein coupling, likely similar to that described for the activated form of the β-adrenergic receptor (15). Recent structural studies of several class B GPCR ECDs and ECD-ligand complexes support this model (16)(17)(18)(19)(20)(21). Glucagon likely interacts with GCGR in a similar fashion to the interaction of other peptide ligands with class B GPC...

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“…5a). It is known that glucagon can activate the GLP-1 receptor with low potency (EC 50 ≈1 nmol/l) [30]. Islet culture supernatant fractions contain glucagon released from alpha cells that could be responsible for activation of the GLP-1 receptor in this assay.…”

Section: Glp-1 Release From Human and Mouse Isletsmentioning

confidence: 96%

Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus—an adaptive response to hyperglycaemia?

et al. 2011

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Different domains of the glucagon and glucagon‐like peptide‐1 receptors provide the critical determinants of ligand selectivity

Cited by 109 publications

References 52 publications

Molecular Approximation between a Residue in the Amino-terminal Region of Calcitonin and the Third Extracellular Loop of the Class B G Protein-coupled Calcitonin Receptor

Molecular Approximation between a Residue in the Amino-terminal Region of Calcitonin and the Third Extracellular Loop of the Class B G Protein-coupled Calcitonin Receptor

Molecular basis for negative regulation of the glucagon receptor

Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus—an adaptive response to hyperglycaemia?

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