Evaluation of Homology Modeling of G-Protein-Coupled Receptors in Light of the A(2A) Adenosine Receptor Crystallographic Structure

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 05/2009; 52(10):3284-92. DOI: 10.1021/jm801533x
Source: PubMed


Homology modeling of the human A(2A) adenosine receptor (AR) based on bovine rhodopsin predicted a protein structure that was very similar to the recently determined crystallographic structure. The discrepancy between the experimentally observed orientation of the antagonist and those obtained by previous antagonist docking is related to the loop structure of rhodopsin being carried over to the model of the A(2A) AR and was rectified when the beta(2)-adrenergic receptor was used as a template 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 A(2A) AR crystallographic structure produced similar results. Heterocyclic nitrogen atoms closely corresponded when the docked adenine moiety of agonists and 1 were overlaid. 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.

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    • "2.64 (in the A 1 receptor), Ile274 7.39 , and His278 7.43 are all involved in binding of ligands, suggesting the importance of this cleft for a range of ligands (Dal Ben et al., 2010; Ivanov et al., 2009). The position of the phenol group in this structure differs from the previous A 2A -T4L structure where it was modeled to point vertically into the solvent-exposed part of the open binding cavity, however, in the A 2A -T4L structure this part of the ligand had higher temperature factors than other parts of the ligand reflecting its flexibility (Jaakola and Ijzerman, 2010; Katritch et al., 2010; Michino et al., 2009). "
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    • "Researchers have successfully applied homology-based of non-rhodopsin GPCRs structure modeling approaches to ligand-binding elucidation [41, 45, 46]. Interestingly, the bigger amount of works based on homology modeling (we found 88 articles by last five years) is dedicated to the rhodopsin-like GPCRs (class A), [47-49] and Taste2 (T2R) GPCRs [43, 50-53]. Several approaches to modeling GPCRs have been described [41], including ab initio [42, 54] and template based [40, 49, 55]. "
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