Thanks to their diversity of functions and widespread expression in all tissues, activation of G-protein-coupled receptors (GPCRs) upon agonist binding plays a critical role in cell signaling in many contexts. The GPCRs are therefore one of the most important classes of protein as drug targets. Recently, the crystal structure of the A2a adenosine receptor bound to agonist adenosine [G. Lebon et al., Nature 474, 521 (2011)] or UK432097 [F. Xu et al., Science 332, 322 (2011)] has been reported, offering insight into receptor A2a ligand binding and activation. Using the crystal structures as a starting point, we performed microsecond-timescale simulations of the A2a receptors bound to adenosine or UK432097, as well as the antagonist ZM241385. Our data suggest that adenosine is highly dynamic when bound to A2a, which contrasts starkly with the larger ligands UK432097 and ZM241385. Analyzing the simulation data in the context of published mutagensis experimental data suggests that the extra molecular scaffold of the larger ligands serves to stabilize key interactions, perhaps rationalizing the relative efficacy of different agonists.

Ligand dynamics during microsecond simulations of the A2a adenosine receptor

243rd National Meeting (2012)

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