MOLECULAR MODELING OF ADENOSINE RECEPTORS - THE LIGAND-BINDING SITE ON THE RAT ADENOSINE A(2A) RECEPTOR

The amino acid sequence of the rat adenosine A(2A) receptor and the at omic coordinates of bacteriorhodopsin were combined to generate a thre e-dimensional model for the adenosine A(2A) receptor. This model consi sts of seven amphipathic alpha-helices, forming a pore that is rather hydrophilic compared to the hydrophobic outside of the protein. Subseq uently, a highly potent and selective ligand for this receptor, 2-(cyc lohexylmethylidinehydrazino)adenosine (SHA 174), was docked into this cavity. A binding site is proposed that takes into account the conform ational characteristics of the ligand. Moreover, it involves two histi dine residues that were shown to be important for ligand coordination from chemical modification studies. Subsequently, the deduced binding site was used to model other potent ligands, including 8-(3-chlorostyr yl)caffeine, a new A(2)-selective antagonist, that could all be accomm odated consistent with earlier biochemical and pharmacological finding s. Finally, some thoughts on how adenosine receptor activation might p roceed are put forward, based on structural analogies with the enzyme family of serine proteases.