A molecular graphics study exploring a putative ligand binding site of the beta-adrenoceptor.

The recent elucidation of the primary structure of the cell membrane-bound beta-adrenoceptor has prompted us to explore putative ligand binding sites on this physiologically important receptor. By minimizing the energies of the 'prototype' ligand propranolol, (part of) the receptor and the proposed ligand-receptor complex with the aid of force field and quantum chemical calculations, we identified amino acid residue Trp313 as a highly probable candidate for interaction with the aromatic moiety of propranolol. The charge distribution on the indole nucleus of another beta-blocker, pindolol, with higher affinity for the beta-adrenoceptor, enables an even stronger interaction with the tryptophan residue. The carboxylic amino acid residue Glu306, located near the extracellular space of the cell membrane, interacts favorably with the positively charged nitrogen atom in the aliphatic side chain of the ligands. Finally, this putative model is discussed in the light of recent findings in mutagenesis studies, and compared to other ideas with respect to ligand-receptor interactions.