Homology modelling of the human adenosine A2B receptor based on X-ray structures of bovine rhodopsin, the β2-adrenergic receptor and the human adenosine A2A receptor

Abstract

A three-dimensional model of the human adenosine A2B receptor was generated by means of homology modelling, using the crystal structures of bovine rhodopsin, the beta2-adrenergic receptor, and the human adenosine A2A receptor as templates. In order to compare the three resulting models, the binding modes of the adenosine A2B receptor antagonists theophylline, ZM241385, MRS1706, and PSB601 were investigated. The A2A-based model was much better able to stabilize the ligands in the binding site than the other models reflecting the high degree of similarity between A2A and A2B receptors: while the A2B receptor shares about 21% of the residues with rhodopsin, and 31% with the beta2-adrenergic receptor, it is 56% identical to the adenosine A2A receptor. The A2A-based model was used for further studies. The model included the transmembrane domains, the extracellular and the intracellular hydrophilic loops as well as the terminal domains. In order to validate the usefulness of this model, a docking analysis of several selective and nonselective agonists and antagonists was carried out including a study of binding affinities and selectivities of these ligands with respect to the adenosine A2A and A2B receptors. A common binding site is proposed for antagonists and agonists based on homology modelling combined with site-directed mutagenesis and a comparison between experimental and calculated affinity data. The new, validated A2B receptor model may serve as a basis for developing more potent and selective drugs.

Challenges and advances in computational docking: 2009 in review

“…Their results have suggested that to best exploit comparative models in molecular docking screens one should use consensus enrichment calculations that include multiple models as well as templates. Others have also addressed issues of docking into homology models (13,(15)(16)(17); for docking into homology models of G-Protein Coupled Receptors (GPCRs), see below.…”

The second extracellular loop of GPCRs determines subtype-selectivity and controls efficacy as evidenced by loop exchange study at A2 adenosine receptors

“…The original 3D homology model of the human A 2B AR was based on the inactive, inverse agonist-bound A 2A AR (3EML) [15,16]. After exchange of the EL2 (the A 2B loop was exchanged for the A 2A loop) the model was energy-minimized again and subjected to molecular dynamics simulation as previously described [14].…”

“…This is particularly true for homology models of closely related receptor subtypes. One example is the A 2B adenosine receptor (A 2B AR) model [14,15], which has been constructed based on X-ray structures of the closely related A 2A AR [16,17].…”

Synthesis, Biological Evaluation and Binding Studies of New Flavone Derivatives as Adenosine A2b Receptor Antagonists

“…The A 2B receptor encodes a protein of 328 to 332 amino acid residues depending on the species [Pierce et al, 1992]. As a result, a new and improved homology model for the human adenosine A 2B receptor was created and investigated [Sherbiny et al, 2009]. Consequently, virtual screening of potential ligands using the adenosine A 2B receptor model has been accomplished.…”

“…The protein target needs to be prepared and modeled according to the format requirements of the docking algorithms used. Thus the homology model of the human A 2B adenosine receptor [Sherbiny et al, 2009] was used. All bound water ligand were removed from the protein prior to the docking process…”