Modeling of the endothelial differentiation gene family, G protein-coupled receptors.

摘要

Endothelial differentiation gene receptors are members of the G protein coupled receptor family. These receptors respond to phospholipid growth factors, sphingosine-1-phosphate (SPP) and lysophosphatidic acid (LPA). Cellular responses include Ca2+ transport, apoptosis, mitogenesis and chemotaxis.; Homology models of the EDG 1, 2, 4, 6 and 7 receptors were developed. Docking studies of the EDG1 model with SPP predicted the interactions of the ligand with the receptor. These interactions, R120, E121 and R292, were experimentally validated by site directed mutagenesis studies. The EDG1 complex was then used to select mutation sites for additional experimental studies. The EDG1 model was then used to develop the other EDG models. The EDG2 model has also been experimentally validated. The Docking studies of the EDG2 model with LPA predicted binding interactions that were confirmed experimentally. These interactions, R124, Q125 and K294, and those of EDG1 with SPP were used to predict that the ligand selectivity of the receptors would be switched by one point mutation (EDG1 E121Q and EDG2 Q125E). This has been confirmed experimentally.