A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures

Wootten, Denise; Reynolds, Christopher A.; Koole, Cassandra; Smith, Kevin J.; Mobarec, Juan Carlos; Simms, John; Quon, Tezz; Coudrat, Thomas; Furness, Sebastian G.B.; Miller, Laurence J.; Christopoulos, Arthur; Sexton, Patrick M.

doi:10.1124/mol.115.101246

Cited by 58 publications

(66 citation statements)

References 53 publications

(83 reference statements)

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“…46 This image suggests that there may be a close contact between the β residue at position 18 of 8 and residues within ECL3 that were previously found to be critical in mediating ERK1/2 phosphorylation induced by GLP-1, exendin-4 and oxyntomodulin via their interactions with the GLP-1R. 26 Oxyntomodulin is biased toward ERK1/2 phosphorylation over cAMP production relative to GLP-1, a selectivity that may arise from the bias of oxyntomodulin toward β-arrestin recruitment.…”

Section: Discussionmentioning

confidence: 99%

β-Arrestin-Biased Agonists of the GLP-1 Receptor from β-Amino Acid Residue Incorporation into GLP-1 Analogues

et al. 2016

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Activation of a G protein-coupled receptor (GPCR) causes recruitment of multiple intracellular proteins, each of which can activate distinct signaling pathways. This complexity has engendered interest in agonists that preferentially stimulate subsets among the natural signaling pathways (“biased agonists”). We have examined analogues of glucagon-like peptide-1 (GLP-1) containing β-amino acid residues in place of native α residues at selected sites and found that some analogues differ from GLP-1 in terms of their relative abilities to promote G protein activation (as monitored via cAMP production) versus β-arrestin recruitment (as monitored via BRET2 assays). The α→β replacements generally cause modest declines in stimulation of cAMP production and β-arrestin recruitment, but for some replacement sets cAMP production is more strongly affected than is β-arrestin recruitment. The central portion of GLP-1 appears to be critical for achieving bias toward β-arrestin recruitment. These results suggest that backbone modification via α→β residue replacement may be a versatile source of agonists with biased GLP-1R activation profiles.

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Section: Discussionmentioning

confidence: 99%

β-Arrestin-Biased Agonists of the GLP-1 Receptor from β-Amino Acid Residue Incorporation into GLP-1 Analogues

et al. 2016

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“…2.60b and E364 6.53b plays a role in GLP-1R ligand-biased signaling (20), emphasizing the important role of this polar H-bond network in both functional activity and ligand recognition by GLP-1R. Table 3 and supplemental Table S5 (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Several N-terminally truncated forms of GLP-1 (53,54), glucagon (55), GIP (56), parathyroid hormone (PTH) (57), and corticotrophin-releasing hormone (CRH) (58) peptides are competitive antagonists for their corresponding receptor, whereas several C-terminally truncated ligands remain active (albeit with lower binding affinity), indicating that interactions with peptide ligands in the 7TM domain of class B GPCRs are required for receptor activation. Differences in the binding modes of the N termini of GLP-1 variants may therefore be important determinants of their functional activity at GLP-1R and control ligand-biased signaling (20).…”

Section: Discussionmentioning

confidence: 99%

“…The accumulated ligand and receptor structure-activity relationships suggest that a flexible conformation of the first seven residues allows the peptide ligands of class B GPCRs to interact with residues deep in the 7TM binding pocket (5) and that the ligand N terminus may adopt a more constrained conformation to activate the receptor as proposed for GLP-1 (18). A central polar hydrogen bond network has been identified in GLP-1R that plays a role in peptide ligand biased signaling (19,20).…”

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Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R)

Yang

Graaf

Yang

et al. 2016

Journal of Biological Chemistry

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The glucagon-like peptide 1 receptor (GLP-1R) 6 and the glucagon receptor (GCGR) are class B G protein-coupled receptors (GPCRs) involved in insulin release and glucose homeostasis, respectively. Accordingly, they have attracted extensive attention for their importance as targets for therapeutic intervention of type 2 diabetes (1, 2). Class B GPCRs consist of an N-terminal extracellular domain (ECD) linked to a seven-transmembrane helical (7TM) region. Studies examining truncated, chimeric, and mutated ligand and receptor variants together with multiple ligand-bound ECD crystal structures and two class B 7TM domain crystal structures are consistent with a "two-domain" binding mechanism for peptide hormone ligands to the secretin-like class B GPCRs (3-5). According to this peptide ligand binding mechanism, the C terminus of the peptide hormone forms an initial complex with the ECD, allowing the N terminus of the ligand to interact with the 7TM domain. It is the N-terminal interactions that ultimately result in activation of the receptor and stimulation of downstream coupling to G proteins and other effectors that mediate intra-*

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“…The most extensive contacts consist of polar and hydrophobic Van der Waals interactions between the receptor and RasGα5-helix (Figure 4a, Extended Data Figure 9a). Class B GPCRs all predominantly couple to Gαs and several of the CTR residues that form interactions with the RasGαs domain are highly conserved and have been implicated in G protein coupling previously 36,37 .…”

Section: The Ctr-gs Interfacementioning

confidence: 99%

Phase-plate cryo-EM structure of a class B GPCR–G-protein complex

Liang

Khoshouei

Radjainia

et al. 2017

Nature

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SUMMARY Class B G protein-coupled receptors are major targets for treatment of chronic diseases, including osteoporosis, diabetes and obesity. Here we report the structure of a full-length class B receptor, the calcitonin receptor, in complex with peptide ligand and heterotrimeric Gαβγs protein determined by Volta phase plate single-particle cryo-electron microscopy. The peptide agonist engages the receptor through binding to an extended hydrophobic pocket facilitated by the large outward movement of the extracellular ends of transmembrane helices 6 and 7. This conformation is accompanied by a 60° kink in helix 6 and large outward movement of the intracellular end of this helix, opening the bundle to accommodate interactions with the α5-helix of Gαs. Also observed is an extended intracellular helix 8 that contributes to both receptor stability and functional G protein coupling via interaction with the Gβ subunit. This structure provides a new framework for understanding G protein-coupled receptor function.

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A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures

Cited by 58 publications

References 53 publications

β-Arrestin-Biased Agonists of the GLP-1 Receptor from β-Amino Acid Residue Incorporation into GLP-1 Analogues

β-Arrestin-Biased Agonists of the GLP-1 Receptor from β-Amino Acid Residue Incorporation into GLP-1 Analogues

Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R)

Phase-plate cryo-EM structure of a class B GPCR–G-protein complex

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