Homology modeling of a Class A GPCR in the inactive conformation: A quantitative analysis of the correlation between model/template sequence identity and model accuracy

J Mol Graph Model. 2016 Nov:70:140-152. doi: 10.1016/j.jmgm.2016.10.004. Epub 2016 Oct 4.


With the present work we quantitatively studied the modellability of the inactive state of Class A G protein-coupled receptors (GPCRs). Specifically, we constructed models of one of the Class A GPCRs for which structures solved in the inactive state are available, namely the β2 AR, using as templates each of the other class members for which structures solved in the inactive state are also available. Our results showed a detectable linear correlation between model accuracy and model/template sequence identity. This suggests that the likely accuracy of the homology models that can be built for a given receptor can be generally forecasted on the basis of the available templates. We also probed whether sequence alignments that allow for the presence of gaps within the transmembrane domains to account for structural irregularities afford better models than the classical alignment procedures that do not allow for the presence of gaps within such domains. As our results indicated, although the overall differences are very subtle, the inclusion of internal gaps within the transmembrane domains has a noticeable a beneficial effect on the local structural accuracy of the domain in question.

Keywords: G protein-coupled receptors; GPCRs; Homology modeling; Sequence alignment; β(2) adrenergic receptor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Models, Molecular*
  • Phylogeny
  • Protein Conformation
  • Receptors, G-Protein-Coupled / chemistry*
  • Sequence Alignment
  • Structural Homology, Protein*


  • Receptors, G-Protein-Coupled