Comparison Analysis of Primary Ligand Binding Sites in Seven-Helical Membrane Proteins

Abstract

Seven-helix transmembrane proteins, including the G-protein coupled receptors, mediate a broad range of fundamental cellular activities through binding to a wide range of ligands. Understanding the structural basis for the ligand-binding selectivity of these proteins is of significance to their structure-based drug design. Comparison analysis of proteins' ligand binding sites provides a useful way to study their structure-activity relationships. Various computational methods have been developed for the binding site comparison of soluble proteins. In this work, we applied this approach to the analysis of the primary ligand-binding sites of 92 seven-helix transmembrane proteins. Results of the studies confirmed that the binding site of bacterial rhodopsins is indeed different from all G-protein coupled receptors. In the latter group, further comparison of the binding sites indicated a group of residues that could be responsible for ligand-binding selectivity and important for structure-based drug design. Further, unexpected binding site dissimilarities were observed among adrenergic and adenosine receptors, suggesting that the percentage of the overall sequence identity between a target protein and a template protein alone is not sufficient for selecting the best template for homology modeling of seven-helix membrane proteins. These results provided novel insight into the structural basis of ligand-binding selectivity of seven-helix membrane proteins and are of practical use to the computational modeling of these proteins.