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J Biol Chem, Vol. 274, Issue 33, 23405-23413, August 13, 1999

Three-dimensional Models of _2A-Adrenergic Receptor Complexes Provide a Structural Explanation for Ligand Binding

Tiina Salminen, Minna Varis, Tommi Nyrönen^**, Marjo Pihlavisto, Anna-Marja Hoffrén^§§, Tuomas Lönnberg^§§, Anne Marjamäki, Heini Frang, Juha-Matti Savola^§§, Mika Scheinin, and Mark S. Johnson

From the  Department of Biochemistry and Pharmacy, Åbo Akademi University and Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Tykistökatu 6 A, FIN-20520 Turku, ^** Center for Scientific Computing (CSC) Tietotie 6, FIN-02101 Espoo, and  Department of Pharmacology and Clinical Pharmacology, Medicity, University of Turku and ^§§ Juvantia Pharma Ltd, Tykistökatu 6 A, FIN-20520 Turku, Finland

We have compared bacteriorhodopsin-based (_2A-AR_BR) and rhodopsin-based (_2A-AR_R) models of the human _2A-adrenengic receptor (_2A-AR) using both docking simulations and experimental receptor alkylation studies with chloroethylclonidine and 2-aminoethyl methanethiosulfonate hydrobromide. The results indicate that the _2A-AR_R model provides a better explanation for ligand binding than does our _2A-AR_BR model. Thus, we have made an extensive analysis of ligand binding to _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 _2A-adrenergic receptor.

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