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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

Vohra, S and Taddese, B and Conner, AC and Poyner, DR and Hay, DL and Barwell, J and Reeves, PJ and Upton, GJG and Reynolds, CA (2013) '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, 10 (79). ISSN 1742-5689

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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. © 2012 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License.

Item Type: Article
Subjects: Q Science > Q Science (General)
Divisions: Faculty of Science and Health > Biological Sciences, School of
Depositing User: Christopher Reynolds
Date Deposited: 31 Jan 2013 18:00
Last Modified: 30 Jan 2019 16:17
URI: http://repository.essex.ac.uk/id/eprint/5435

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