title: Human A3 adenosine receptor as versatile G protein-coupled receptor example to validate the receptor homology modeling technology.
abstract: The development of ligands for the A(3) adenosine receptor (AR) has been directed mainly by traditional medicinal chemistry, but the influence of structure-based approaches is increasing. Rhodopsin-based homology modeling had been used for many years to obtain three-dimensional models of the A(3)AR, and different A(3)AR models have been published describing the hypothetical interactions with known A(3)AR ligands having different chemical scaffolds. The recently published structure of the human A(2A)AR provides a new template for GPCR modeling, however even use of the A(2A)AR as a template for modeling other AR subtypes is still imprecise. The models compared here are based on bovine rhodopsin, the human beta(2)-adrenergic receptor, and the A(2A)AR as templates. The sequence of the human A(3)AR contains only one cysteine residue (Cys166) in the second extracellular loop (EL2), which putatively forms a conserved disulfide bridge with the respective cysteine residues of TM3 (Cys83). Homology models of the A(3)AR have been helpful in providing structural hypotheses for the design of new ligands. Site-directed mutagenesis of the A(3)AR shows an important role in ligand recognition for specific residues in TM3, TM6 and TM7.
authors.affiliation: Molecular Modeling Section (MMS), Department of Pharmaceutical Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: Erika
authors.initials: E
authors.lastname: Morizzo
authors.forename: Stephanie
authors.initials: S
authors.lastname: Federico
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
authors.forename: Stefano
authors.initials: S
authors.lastname: Moro
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D043684:Receptor, Adenosine A3 / Q000737:chemistry* / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000737:chemistry; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D012243:Rhodopsin / Q000737:chemistry
chemical_list: D008024:Ligands; D043684:Receptor, Adenosine A3; D043683:Receptors, Adenosine A2; D018343:Receptors, Adrenergic, beta-2; D012243:Rhodopsin