A2A Adenosine Receptor Partial Agonism Related to Structural Rearrangements in an Activation Microswitch.

ABSTRACT

In drug design, G protein-coupled receptor (GPCR) partial agonists enable one to fine-tune receptor output between basal and maximal signaling levels. Here, we add to the structural basis for rationalizing and monitoring partial agonism. NMR spectroscopy of partial agonist complexes of the A2A adenosine receptor (A2AAR) revealed conformations of the P-I-F activation motif that are distinctly different from full agonist complexes. At the intracellular surface, different conformations of helix VI observed for partial and full agonist complexes manifest a correlation between the efficacy-related structural rearrangement of this activation motif and intracellular signaling to partner proteins. While comparisons of A2AAR in complexes with partial and full agonists with different methods showed close similarity of the global folds, this NMR study now reveals subtle but distinct local structural differences related to partial agonism.