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Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy.

Dal Maso, Emma and Zhu, Yue and Pham, Vi and Reynolds, Christopher A and Deganutti, Giuseppe and Hick, Caroline A and Yang, Dehua and Christopoulos, Arthur and Hay, Debbie L and Wang, Ming-Wei and Sexton, Patrick M and Furness, Sebastian GB and Wootten, Denise (2018) 'Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy.' Biochemical Pharmacology, 150. pp. 214-244. ISSN 0006-2952

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Class B peptide hormone GPCRs are targets for the treatment of major chronic disease. Peptide ligands of these receptors display biased agonism and this may provide future therapeutic advantage. Recent active structures of the calcitonin (CT) and glucagon-like peptide-1 (GLP-1) receptors reveal distinct engagement of peptides with extracellular loops (ECLs) 2 and 3, and mutagenesis of the GLP-1R has implicated these loops in dynamics of receptor activation. In the current study, we have mutated ECLs 2 and 3 of the human CT receptor (CTR), to interrogate receptor expression, peptide affinity and efficacy. Integration of these data with insights from the CTR and GLP-1R active structures, revealed marked diversity in mechanisms of peptide engagement and receptor activation between the CTR and GLP-1R. While the CTR ECL2 played a key role in conformational propagation linked to Gs/cAMP signalling this was mechanistically distinct from that of GLP-1R ECL2. Moreover, ECL3 was a hotspot for distinct ligand- and pathway- specific effects, and this has implications for the future design of biased agonists of class B GPCRs.

Item Type: Article
Uncontrolled Keywords: G protein-coupled receptor; Calcitonin receptor; GPCR structure-function; Biased agonism; Molecular modelling
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 22 Feb 2018 13:59
Last Modified: 06 Jan 2022 13:48

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