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.
| Original language | English |
|---|---|
| Pages (from-to) | 214-244 |
| Number of pages | 31 |
| Journal | Biochemical Pharmacology |
| Volume | 150 |
| DOIs | |
| Publication status | Published - 1 Apr 2018 |
Keywords
- Biased agonism
- Calcitonin receptor
- G protein-coupled receptor
- GPCR structure-function
- Molecular modelling
Cite this
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Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy. / Dal Maso, Emma; Zhu, Yue; Pham, Vi; Reynolds, Christopher A.; Deganutti, Giuseppe; Hick, Caroline A.; Yang, Dehua; Christopoulos, Arthur; Hay, Debbie L.; Wang, Ming Wei; Sexton, Patrick M.; Furness, Sebastian G.B.; Wootten, Denise.
In: Biochemical Pharmacology, Vol. 150, 01.04.2018, p. 214-244.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy
AU - Dal Maso, Emma
AU - Zhu, Yue
AU - Pham, Vi
AU - Reynolds, Christopher A.
AU - Deganutti, Giuseppe
AU - Hick, Caroline A.
AU - Yang, Dehua
AU - Christopoulos, Arthur
AU - Hay, Debbie L.
AU - Wang, Ming Wei
AU - Sexton, Patrick M.
AU - Furness, Sebastian G.B.
AU - Wootten, Denise
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
KW - Biased agonism
KW - Calcitonin receptor
KW - G protein-coupled receptor
KW - GPCR structure-function
KW - Molecular modelling
UR - http://www.scopus.com/inward/record.url?scp=85042481521&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2018.02.005
DO - 10.1016/j.bcp.2018.02.005
M3 - Article
VL - 150
SP - 214
EP - 244
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
ER -