title: Communication over the network of binary switches regulates the activation of A2A adenosine receptor.
abstract: Dynamics and functions of G-protein coupled receptors (GPCRs) are accurately regulated by the type of ligands that bind to the orthosteric or allosteric binding sites. To glean the structural and dynamical origin of ligand-dependent modulation of GPCR activity, we performed total ~ 5 μsec molecular dynamics simulations of A2A adenosine receptor (A2AAR) in its apo, antagonist-bound, and agonist-bound forms in an explicit water and membrane environment, and examined the corresponding dynamics and correlation between the 10 key structural motifs that serve as the allosteric hotspots in intramolecular signaling network. We dubbed these 10 structural motifs "binary switches" as they display molecular interactions that switch between two distinct states. By projecting the receptor dynamics on these binary switches that yield 2(10) microstates, we show that (i) the receptors in apo, antagonist-bound, and agonist-bound states explore vastly different conformational space; (ii) among the three receptor states the apo state explores the broadest range of microstates; (iii) in the presence of the agonist, the active conformation is maintained through coherent couplings among the binary switches; and (iv) to be most specific, our analysis shows that W246, located deep inside the binding cleft, can serve as both an agonist sensor and actuator of ensuing intramolecular signaling for the receptor activation. Finally, our analysis of multiple trajectories generated by inserting an agonist to the apo state underscores that the transition of the receptor from inactive to active form requires the disruption of ionic-lock in the DRY motif.
authors: National Leading Research Laboratory (NLRL) of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Korea.
authors: Yoonji
authors: Y
authors: Lee
authors: National Leading Research Laboratory (NLRL) of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Korea.
authors: Sun
authors: S
authors: Choi
authors: School of Computational Sciences, Korea Institute for Advanced Study, Seoul 130-722, Korea.
authors: Changbong
authors: C
authors: Hyeon
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry / Q000378:metabolism*; D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D021122:Protein Subunits; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D021122:Protein Subunits; D043705:Receptor, Adenosine A2A