MODELING OF HUMAN THROMBOXANE-A(2) RECEPTOR AND ANALYSIS OF THE RECEPTOR LIGAND INTERACTION

In order to elucidate the mode of the thromboxane A2 (TXA2) receptor-ligand interaction at the molecular level, a model for the human TXA2 receptor, a member of the G protein-coupled receptor family with seven transmembrane segments, was constructed on the basis of its amino acid sequence, which was determined recently (Hirata, M.; et al. Nature 1991, 349, 617-620). First, we made a model for the human beta2-adrenergic receptor using its amino acid sequence and the known helix arrangement of bacteriorhodopsin. Then, a TXA2 receptor model was constructed based on the beta2 receptor model and was used to analyze the receptor-ligand interaction. The ligand-binding pocket of the TXA2 receptor includes a serine residue from segment V, an arginine residue from segment VII, and a large hydrophobic pocket between these two residues. These results are consistent with the known properties of TXA2 and TXA2 antagonists having a hydrogen-bonding group such as hydroxyl, a carboxyl group, and a hydrophobic moiety. This model should be helpful for rational design of potent TXA2 antagonists.