Wootten, Denise and Reynolds, Christopher A and Smith, Kevin J and Mobarec, Juan C and Furness, Sebastian GB and Miller, Laurence J and Christopoulos, Arthur and Sexton, Patrick M (2016) Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor. Biochemical Pharmacology, 118. pp. 68-87. DOI https://doi.org/10.1016/j.bcp.2016.08.015
Wootten, Denise and Reynolds, Christopher A and Smith, Kevin J and Mobarec, Juan C and Furness, Sebastian GB and Miller, Laurence J and Christopoulos, Arthur and Sexton, Patrick M (2016) Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor. Biochemical Pharmacology, 118. pp. 68-87. DOI https://doi.org/10.1016/j.bcp.2016.08.015
Wootten, Denise and Reynolds, Christopher A and Smith, Kevin J and Mobarec, Juan C and Furness, Sebastian GB and Miller, Laurence J and Christopoulos, Arthur and Sexton, Patrick M (2016) Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor. Biochemical Pharmacology, 118. pp. 68-87. DOI https://doi.org/10.1016/j.bcp.2016.08.015
Abstract
Class B GPCRs can activate multiple signalling effectors with the potential to exhibit biased agonism in response to ligand stimulation. Previously, we highlighted key TM domain polar amino acids that were crucial for the function of the GLP-1 receptor, a key therapeutic target for diabetes and obesity. Using a combination of mutagenesis, pharmacological characterisation, mathematical and computational molecular modelling, this study identifies additional highly conserved polar residues located towards the TM helical boundaries of Class B GPCRs that are important for GLP-1 receptor stability and/or controlling signalling specificity and biased agonism. This includes (i) three positively charged residues (R3.30227, K4.64288, R5.40310) located at the extracellular boundaries of TMs 3, 4 and 5 that are predicted in molecular models to stabilise extracellular loop 2, a crucial domain for ligand affinity and receptor activation; (ii) a predicted hydrogen bond network between residues located in TMs 2 (R2.46176), 6 (R6.37348) and 7 (N7.61406 and E7.63408) at the cytoplasmic face of the receptor that is important for stabilising the inactive receptor and directing signalling specificity, (iii) residues at the bottom of TM 5 (R5.56326) and TM6 (K6.35346 and K6.40351) that are crucial for receptor activation and downstream signalling; (iv) residues predicted to be involved in stabilisation of TM4 (N2.52182 and Y3.52250) that also influence cell signalling. Collectively, this work expands our understanding of peptide-mediated signalling by the GLP-1 receptor.
Item Type: | Article |
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Uncontrolled Keywords: | Glucagon-like peptide-1 receptor; Biased agonism; G protein-coupled receptor; Cell signaling |
Subjects: | Q Science > QH Natural history > QH301 Biology |
Divisions: | Faculty of Science and Health Faculty of Science and Health > Life Sciences, School of |
SWORD Depositor: | Unnamed user with email elements@essex.ac.uk |
Depositing User: | Unnamed user with email elements@essex.ac.uk |
Date Deposited: | 26 Aug 2016 14:24 |
Last Modified: | 07 Aug 2024 19:54 |
URI: | http://repository.essex.ac.uk/id/eprint/17472 |
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