Evaluation of Homology Modeling of G Protein-Coupled Receptors in Light of the A2A Adenosine Receptor Crystallographic Structure

摘要

Homology modeling of the human A2A adenosine receptor (AR) based on bovine rhodopsin predicted a protein structure that was very similar to the recently determined crystallographic structure. The inaccuracy of previous antagonist docking is related to the loop structure of rhodopsin being carried over to the model of the A2A AR and was rectified when the β2-adrenergic receptor was used as a template is used for homology modeling. Docking of the triazolotriazine antagonist ligand ZM241385 >1 was greatly improved by including water molecules of the X-ray structure or by using a constraint from mutagenesis. Automatic agonists docking to both a new homology modeled receptor and the A2A AR crystallographic structure produced similar results. Heterocyclic nitrogen atoms closely corresponded when the docked adenine moiety of agonists and >1 were overlayed. The cumulative mutagenesis data, which support the proposed mode of agonist docking, can be reexamined in light of the crystallographic structure. Thus, homology modeling of GPCRs remains a useful technique in probing the structure of the protein and predicting modes of ligand docking.