A full picture of the similarities between Family A and Family B GPCRs (G-protein coupled receptors) has been frustrated by the lack of clear homology between the respective sequences. Here, we review previous computational studies on GPCR dimerization in which the putative dimerization interfaces have been analysed using entropy, the ET (evolutionary trace) method and related methods. The results derived from multiple sequence alignments of Family A subfamilies have been mapped on to the rhodopsin crystal structure using standard alignments. Similarly, the results for the Family B alignments have been mapped on to the rhodopsin crystal structure using the ‘cold-spot’ alignment. For both Family A and Family B GPCRs, the sequence analysis indicates that there are functional sites on essentially all transmembrane helices, consistent with the parallel daisy chain model of GPCR oligomerization in which each GPCR makes interactions with a number of neighbouring GPCRs. The results are not too sensitive to the quality of the alignment. Molecular Dynamics simulations of the activation process within a single transmembrane bundle of the rhodopsin and the β2-adrenergic receptor have been reviewed; the key observation, which is consistent with other computational studies, is that there is a translation and bending of helix 6, which contributes to a significant opening out of the intracellular face of the receptor, as shown in the accompanying movies. The simulations required the application of specific experiment-derived harmonic and half-harmonic distance restraints and so the application of such simulations to Family B GPCRs requires considerable care because of the alignment problem. Thus, in order to address the alignment problem, we have exploited the observation that GCR1, a plant GPCR, has homology with Family A, Family B and Family E GPCRs. The resulting alignment for transmembrane helix 3 is presented.
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August 2007
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Conference Article|
July 20 2007
Computational studies of Family A and Family B GPCRs
S. Vohra;
S. Vohra
*Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, U.K.
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S.V. Chintapalli;
S.V. Chintapalli
*Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, U.K.
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C.J.R. Illingworth;
C.J.R. Illingworth
*Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, U.K.
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P.J. Reeves;
P.J. Reeves
*Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, U.K.
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P.M. Mullineaux;
P.M. Mullineaux
*Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, U.K.
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H.S.X. Clark;
H.S.X. Clark
*Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, U.K.
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M.K. Dean;
M.K. Dean
*Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, U.K.
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G.J.G. Upton;
G.J.G. Upton
†Department of Mathematical Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, U.K.
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C.A. Reynolds
C.A. Reynolds
1
*Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, U.K.
1To whom correspondence should be addressed (email C.A.Reynolds@essex.ac.uk).
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Publisher: Portland Press Ltd
Received:
May 04 2007
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2007 Biochemical Society
2007
Biochem Soc Trans (2007) 35 (4): 749–754.
Article history
Received:
May 04 2007
Citation
S. Vohra, S.V. Chintapalli, C.J.R. Illingworth, P.J. Reeves, P.M. Mullineaux, H.S.X. Clark, M.K. Dean, G.J.G. Upton, C.A. Reynolds; Computational studies of Family A and Family B GPCRs. Biochem Soc Trans 1 August 2007; 35 (4): 749–754. doi: https://doi.org/10.1042/BST0350749
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