New vistas in GPCR 3D structure prediction

Human G-protein coupled receptors (hGPCRs) comprise the most prominent family of validated drug targets. More than 50% of approved drugs reveal their therapeutic effects by targeting this family. Accurate models would greatly facilitate the process of drug discovery and development. However, 3-D structure prediction of GPCRs remains a challenge due to limited availability of resolved structure. The X-ray structures have been solved for only four such proteins. The identity between hGPCRs and the potential templates is mostly less than 30%, well below the level at which sequence alignment can be done regularly. In this study, we analyze a large database of human G-protein coupled receptors that are members of family A in order to optimize usage of the available crystal structures for molecular modeling of hGPCRs. On the basis of our findings in this study, we propose to regard specific parts from the trans-membrane domains of the reference receptor helices as appropriate template for constructing models of other GPCRs, while other residues require other techniques for their remodeling and refinement. The proposed hypothesis in the current study has been tested by modeling human β2-adrenergic receptor based on crystal structures of bovine rhodopsin (1F88) and human A2A adenosine receptor (3EML). The results have shown some improvement in the quality of the predicted models compared to Modeller software.