Journal
JOURNAL OF THE ROYAL SOCIETY INTERFACE
Volume 10, Issue 88, Pages -Publisher
ROYAL SOC
DOI: 10.1098/rsif.2013.0589
Keywords
calcitonin gene-related peptide; class B G-protein-coupled receptor; loop modelling; site-directed mutagenesis; calcitonin receptor-like receptor
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Funding
- Wellcome Trust [091496]
- New Zealand Heart Foundation
- MRC [G1001812]
- MRC [G1001812] Funding Source: UKRI
- British Heart Foundation [PG/12/59/29795] Funding Source: researchfish
- Medical Research Council [G1001812] Funding Source: researchfish
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The calcitonin gene-related peptide (CGRP) receptor is a complex of a calcitonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271-294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2-modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely structures for receptor activation are discussed.
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