Rhodopsin is the only member of the G protein-coupled receptors (GPCRs) superfamily for which crystallographic data are available. Thus, the study of the structure-function relationships of most GPCRs relies on bioinformatics, rhodopsin-based homology modeling, and docking experiments conducted in an iterative manner utilizing site-directed mutagenesis and chemical modification of the ligands. Adenosine receptors (ARs) are presented as a case study to illustrate this indirect composite approach relying on an intimate combination of computational and experimental techniques. In the first section we discuss the phylogenesis of the ARs from an evolutionary perspective. Furthermore, we review sequence comparison studies from the perspective of similarities with other GPCRs, chemogenomics, and coupling to G proteins. In the second section, we review various rhodopsin-based homology models of the ARs and docking studies of agonists and antagonists. As reported for other GPCRs, several different modes have been hypothesized for ligands binding to ARs. Here, we critically review the proposed binding modes of agonists and antagonists in light of the available mutagenesis data and the structure-activity relationships of ligands. Lastly, we review an experimentally-supported strategy for validating theoretical binding hypotheses based on the complementary reengineering of receptors and ligands (neoceptors and neoligands).
