Three-dimensional models of α(2A)-adrenergic receptor complexes provide a structural explanation for ligand binding

Abstract

We have compared bacteriorhodopsin-based (α(2A)-AR(BR)) and rhodopsin- based (α(2A)-AR(R)) models of the human α(2A)-adrenengic receptor (α(2A)- AR) using both docking simulations and experimental receptor alkylation studies with chloroethylclonidine and 2-aminoethyl methanethiosulfonate hydrobromide. The results indicate that the α(2A)-AR(R) model provides a better explanation for ligand binding than does our α(2A)-AR(BR) model. Thus, we have made an extensive analysis of ligand binding to α(2A)-AR(R) and engineered mutant receptors using clonidine, para-aminoclonidine, oxymetazoline, 5-bromo-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14,304), and norepinephrine as ligands. The representative docked ligand conformation was chosen using extensive docking simulations coupled with the identification of favorable interaction sites for chemical groups in the receptor. These ligand-protein complex studies provide a rational explanation at the atomic level for the experimentally observed binding affinities of each of these ligands to the α(2A)-adrenergic receptor.