title: Predicted 3D structures for adenosine receptors bound to ligands: comparison to the crystal structure.
abstract: G protein-coupled receptors (GPCRs) are therapeutic targets for many diseases, but progress in developing active and selective therapeutics has been severely hampered by the difficulty in obtaining accurate structures. We have been developing methods for predicting the structures for GPCR ligand complexes, but validation has been hampered by a lack of experimental structures with which to compare our predictions. We report here the predicted structures of the human adenosine GPCR subtypes (A(1), A(2A), A(2B), and A(3)) and the binding sites for adenosine agonist and eight antagonists to this predicted structure, making no use of structural data, and compare with recent experimental crystal structure for ZM241385 bound human A(2A) receptor. The predicted structure correctly identifies 9 of the 12 crystal binding site residues. Moreover, the predicted binding energies of eight antagonists to the predicted structure of A(2A) correlate quite well with experiment. These excellent predictions resulted when we used Monte Carlo techniques to optimize the loop structures, particularly the cysteine linkages. Ignoring these linkages led to a much worse predicted binding site (identifying only 3 of the 12 important residues). These results indicate that computational methods can predict the three-dimensional structure of GPCR membrane proteins sufficiently accurately for use in designing subtype selective ligands for important GPCR therapeutics targets.
authors.affiliation: Materials and Process Simulation Center (MC139-74), California Institute of Technology, 1200 E. California Blvd., Pasadena, CA 91125, USA. wag@wag.caltech.edu
authors.forename: William A
authors.initials: WA
authors.lastname: Goddard
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Kim
authors.forename: Youyong
authors.initials: Y
authors.lastname: Li
authors.forename: Bartosz
authors.initials: B
authors.lastname: Trzaskowski
authors.forename: Adam R
authors.initials: AR
authors.lastname: Griffith
authors.forename: Ravinder
authors.initials: R
authors.lastname: Abrol
mesh_terms: D001665:Binding Sites / Q000235:genetics; D003460:Crystallization; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009010:Monte Carlo Method; D011487:Protein Conformation; D043705:Receptor, Adenosine A2A / Q000737:chemistry*; D014227:Triazines; D014230:Triazoles
chemical_list: D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385