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The role of ECL2 in CGRP receptor activation : a combined modelling and experimental approach
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Woolley, Michael J., Watkins, Harriet A., Taddese, Bruck, Karakullukcu, Z. Gamze, Barwell, James, Smith, Kevin J., Hay, Debbie L., Poyner, David, Reynolds, Christopher A. and Conner, Alex C. (2013) The role of ECL2 in CGRP receptor activation : a combined modelling and experimental approach. Journal of The Royal Society Interface, Volume 10 (Number 88). p. 20130589. doi:10.1098/rsif.2013.0589 ISSN 1742-5689.
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WRAP_J. R. Soc. Interface-2013-Woolley-.pdf - Published Version Download (1397Kb) | Preview |
Official URL: http://dx.doi.org/10.1098/rsif.2013.0589
Abstract
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.
| Item Type: | Journal Article | ||||
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| Subjects: | Q Science > QH Natural history > QH301 Biology Q Science > QH Natural history > QH426 Genetics |
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| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School | ||||
| Library of Congress Subject Headings (LCSH): | Genetics -- Research, Calcitonin gene-related peptide, G proteins, Site-specific mutagenesis | ||||
| Journal or Publication Title: | Journal of The Royal Society Interface | ||||
| Publisher: | The Royal Society Publishing | ||||
| ISSN: | 1742-5689 | ||||
| Official Date: | 2013 | ||||
| Dates: |
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| Volume: | Volume 10 | ||||
| Number: | Number 88 | ||||
| Page Range: | p. 20130589 | ||||
| DOI: | 10.1098/rsif.2013.0589 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||
| Date of first compliant deposit: | 23 June 2016 | ||||
| Date of first compliant Open Access: | 23 June 2016 | ||||
| Funder: | Wellcome Trust (London, England), National Heart Foundation of New Zealand (NHFNZ), Medical Research Council (Great Britain) (MRC) | ||||
| Grant number: | 091496 (WT) ; G1001812 (MRC) |
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