Ap. Ijzerman et al., MOLECULAR MODELING OF ADENOSINE RECEPTORS - THE LIGAND-BINDING SITE ON THE RAT ADENOSINE A(2A) RECEPTOR, European journal of pharmacology. Molecular pharmacology section, 268(1), 1994, pp. 95-104
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.