title: Predicted structures of agonist and antagonist bound complexes of adenosine A3 receptor.
abstract: We used the GEnSeMBLE Monte Carlo method to predict ensemble of the 20 best packings (helix rotations and tilts) based on the neutral total energy (E) from a vast number (10 trillion) of potential packings for each of the four subtypes of the adenosine G protein-coupled receptors (GPCRs), which are involved in many cytoprotective functions. We then used the DarwinDock Monte Carlo methods to predict the binding pose for the human A(3) adenosine receptor (hAA(3)R) for subtype selective agonists and antagonists. We found that all four A(3) agonists stabilize the 15th lowest conformation of apo-hAA(3)R while also binding strongly to the 1st and 3rd. In contrast the four A(3) antagonists stabilize the 2nd or 3rd lowest conformation. These results show that different ligands can stabilize different GPCR conformations, which will likely affect function, complicating the design of functionally unique ligands. Interestingly all agonists lead to a trans χ1 angle for W6.48 that experiments on other GPCRs associate with G-protein activation while all 20 apo-AA(3)R conformations have a W6.48 gauche+ χ1 angle associated experimentally with inactive GPCRs for other systems. Thus docking calculations have identified critical ligand-GPCR structures involved with activation. We found that the predicted binding site for selective agonist Cl-IB-MECA to the predicted structure of hAA(3)R shows favorable interactions to three subtype variable residues, I253(6.58), V169(EL2), and Q167(EL2), while the predicted structure for hAA(2A)R shows weakened to the corresponding amino acids: T256(6.58), E169(EL2), and L167(EL2), explaining the observed subtype selectivity.
authors.affiliation: Division of Chemistry and Chemical Engineering, Materials and Process Simulation Center MC139-74, California Institute of Technology, Pasadena, California 91125, USA.
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Kim
authors.forename: Lindsay
authors.initials: L
authors.lastname: Riley
authors.forename: Ravinder
authors.initials: R
authors.lastname: Abrol
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: William A
authors.initials: WA
authors.lastname: Goddard
mesh_terms: D058909:Adenosine A3 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology; D058918:Adenosine A3 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology; D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D011485:Protein Binding; D043684:Receptor, Adenosine A3 / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D043684:Receptor, Adenosine A3