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Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies
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Vohra, Shabana, Taddese, Bruck, Conner, Alex C., Poyner, David, Hay, Debbie L., Barwell, James, Reeves, Philip J., Upton, Graham J. G. and Reynolds, Christopher A. (2012) Similarity between class A and class B G-protein-coupled receptors exemplified through calcitonin gene-related peptide receptor modelling and mutagenesis studies. Journal of The Royal Society Interface, Volume 10 (Number 79). Article no. 20120846. doi:10.1098/rsif.2012.0846
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WRAP_Connor_J. R. Soc. Interface-2013-Vohra-.pdf - Published Version Available under License Creative Commons Attribution Non-commercial. Download (1744Kb) | Preview |
Official URL: http://dx.doi.org/10.1098/rsif.2012.0846
Abstract
Modelling class B G-protein-coupled receptors (GPCRs) using class A GPCR structural templates is difficult due to lack of homology. The plant GPCR, GCR1, has homology to both class A and class B GPCRs. We have used this to generate a class A–class B alignment, and by incorporating maximum lagged correlation of entropy and hydrophobicity into a consensus score, we have been able to align receptor transmembrane regions. We have applied this analysis to generate active and inactive homology models of the class B calcitonin gene-related peptide (CGRP) receptor, and have supported it with site-directed mutagenesis data using 122 CGRP receptor residues and 144 published mutagenesis results on other class B GPCRs. The variation of sequence variability with structure, the analysis of polarity violations, the alignment of group-conserved residues and the mutagenesis results at 27 key positions were particularly informative in distinguishing between the proposed and plausible alternative alignments. Furthermore, we have been able to associate the key molecular features of the class B GPCR signalling machinery with their class A counterparts for the first time. These include the [K/R]KLH motif in intracellular loop 1, [I/L]xxxL and KxxK at the intracellular end of TM5 and TM6, the NPXXY/VAVLY motif on TM7 and small group-conserved residues in TM1, TM2, TM3 and TM7. The equivalent of the class A DRY motif is proposed to involve Arg2.39, His2.43 and Glu3.46, which makes a polar lock with T6.37. These alignments and models provide useful tools for understanding class B GPCR function.
| Item Type: | Journal Article | ||||
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| Subjects: | Q Science > QC Physics Q Science > QD Chemistry Q Science > QH Natural history > QH301 Biology |
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| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Biochemistry -- Research, Biophysics -- Research, Molecular biology -- Mathematical models, Cell receptors, Binding sites (Biochemistry), Cell membranes, Proteins | ||||
| Journal or Publication Title: | Journal of The Royal Society Interface | ||||
| Publisher: | The Royal Society Publishing | ||||
| ISSN: | 1742-5689 | ||||
| Official Date: | 2012 | ||||
| Dates: |
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| Volume: | Volume 10 | ||||
| Number: | Number 79 | ||||
| Page Range: | Article no. 20120846 | ||||
| DOI: | 10.1098/rsif.2012.0846 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Open Access | ||||
| Funder: | Wellcome Trust (London, England), Medical Research Council (Great Britain) (MRC) | ||||
| Grant number: | 091496 (WT), G1001812 |
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