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

Emma Dal Maso; Yue Zhu; Vi Pham; Christopher A. Reynolds; Giuseppe Deganutti; Caroline A. Hick; Dehua Yang; Arthur Christopoulos; Debbie L. Hay; Ming Wei Wang; Patrick M. Sexton; Sebastian G.B. Furness; Denise Wootten

doi:10.1016/j.bcp.2018.02.005

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

Emma Dal Maso
, Yue Zhu
, Vi Pham
, Christopher A. Reynolds
, Giuseppe Deganutti
, Caroline A. Hick
, Dehua Yang
, Arthur Christopoulos
, Debbie L. Hay
, Ming Wei Wang
, Patrick M. Sexton
, Sebastian G.B. Furness
, Denise Wootten

Shanghai Institute of Materia Medica
University of Chinese Academy of Sciences
University of Essex
University of Auckland
Fudan University
Monash University

Research output: Contribution to journal › Article › peer-review

26 Citations (Scopus)

82 Downloads (Pure)

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
Early online date	16 Feb 2018
DOIs	https://doi.org/10.1016/j.bcp.2018.02.005
Publication status	Published - Apr 2018
Externally published	Yes

Bibliographical note

Funding

This work was supported by National Health and Medical Research Council of Australia (NHMRC) project grants ( 1061044 , 1065410 and 1126857 ), NHMRC program grant ( 1055134 ), Shanghai Science and Technology Development Fund ( 15DZ2291600 ), the Chinese Academy of Sciences (CAS)- Novo Nordisk Research Fund , and the United Kingdom Biotechnology Biological Sciences Research Council ( BB/M006883/1 ). DW is a NHMRC Career Development Fellow, PMS is a NHMRC Principal Research Fellow and AC is a NHMRC Senior Principal Research Fellow. CAR is a Royal Society Industrial Fellow and DLH is a James Cook Research Fellow of the Royal Society of New Zealand.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

ASJC Scopus subject areas

Biochemistry
Pharmacology

Access to Document

10.1016/j.bcp.2018.02.005Licence: CC BY

Post-PrintFinal published version, 10.8 MBLicence: CC BY

Cite this

Dal Maso, E., Zhu, Y., Pham, V., Reynolds, C. A., Deganutti, G., Hick, C. A., Yang, D., Christopoulos, A., Hay, D. L., Wang, M. W., Sexton, P. M., Furness, S. G. B., & Wootten, D. (2018). Extracellular loops 2 and 3 of the calcitonin receptor selectively modify agonist binding and efficacy. Biochemical Pharmacology, 150, 214-244. https://doi.org/10.1016/j.bcp.2018.02.005

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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.",

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doi = "10.1016/j.bcp.2018.02.005",

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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

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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Fingerprint

Giuseppe Deganutti

Cite this

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Profiles

Giuseppe Deganutti

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