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Biochem Pharmacol. 2018 Apr;150:214-244. doi: 10.1016/j.bcp.2018.02.005. Epub 2018 Feb 16.

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

Author information

1
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia.
2
The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
3
School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, United Kingdom.
4
The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
5
The University of Auckland, School of Biological Sciences, 3 Symonds Street, Auckland 1142, New Zealand.
6
The National Center for Drug Screening and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmacy, Fudan University, Shanghai 201203, China.
7
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia; School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: Patrick.sexton@monash.edu.
8
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia. Electronic address: Sebastian.furness@monash.edu.
9
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville 3052, Victoria, Australia. Electronic address: denise.wootten@monash.edu.

Abstract

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.

KEYWORDS:

Biased agonism; Calcitonin receptor; G protein-coupled receptor; GPCR structure-function; Molecular modelling

PMID:
29454620
PMCID:
PMC5908784
DOI:
10.1016/j.bcp.2018.02.005
[Indexed for MEDLINE]
Free PMC Article

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