Computational studies of Family A and Family B GPCRs

Vohra, S., Chintapalli, S.V., Illingworth, C.J.R. , Reeves, P.J., Mullineaux, P.M., Clark, H.S.X., Dean, M.K., Upton, G.J.G. and Reynolds, C.A. (2007) Computational studies of Family A and Family B GPCRs. Biochemical Society Transactions, 35(4), pp. 749-754. (doi: 10.1042/BST0350749) (PMID:17635140)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Illingworth, Dr Chris
• Authors: Vohra, S., Chintapalli, S.V., Illingworth, C.J.R., Reeves, P.J., Mullineaux, P.M., Clark, H.S.X., Dean, M.K., Upton, G.J.G., and Reynolds, C.A.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Biochemical Society Transactions
• Publisher: Portland Press
• ISSN: 0300-5127