Abstract
Despite recent progress in structural coverage of the G-protein-coupled receptor (GPCR) family, high plasticity of these membrane proteins poses additional challenges for crystallographic studies of their complexes with different classes of ligands, especially agonists. The ability to predict computationally the binding of natural and clinically relevant agonists and corresponding changes in the receptor pocket, starting from inactive GPCR structures, is therefore of great interest for understanding GPCR biology and drug action. Comparison of computational models published in 2009 and 2010 with recently determined agonist-bound structures of β-adrenergic and adenosine A(2A) receptors reveals high accuracy of the predicted agonist binding poses (0.8 Å and 1.7 Å respectively) and receptor interactions. In the case of the β(2)AR, energy-based models with limited backbone flexibility have also allowed characterization of side-chain rotations and a finite backbone shift in the pocket region as determinants of full, partial or inverse agonism. Development of accurate models of agonist binding for other GPCRs will be instrumental for functional and pharmacological studies, complementing biochemical and crystallographic techniques.