Ligand-Perturbed Allosteric Communication within the Human A2A Adenosine Receptor

Abstract

The human A2A adenosine receptor (A2AR) is a member of Class A G protein-coupled receptors (GPCRs). Activation of A2A adenosine receptor leads to the stimulation of adenylyl cyclase (AC), and thereby increases the formation of cyclic adenosine monophosphate (cAMP). It has been recognized that A2A adenosine receptor is a potential therapeutic target for the treatment of Parkinson's disease, Huntington's disease, schizophrenia, and other neurodegenerative diseases. In 2008, the first human A2A adenosine receptor was crystalized in complex with its high affinity selective antagonist ZM241385. In 2011, six more A2A adenosine receptor structures were published. Three of them co-crystallized with its agonists (UK432097, adenosine, and NECA) and three of the others co-crystallized with its antagonists (ZM241385, xanthine amine congener, and caffeine). In this study, the changes of allosteric communication inside the A2A adenosine receptor induced by these agonists and antagonists are examined by molecular dynamics simulations. We found that agonists are able to switch the torsion angle of W2466.48, and the correlated motions within the A2A adenosine receptor are also perturbed by this rotamer toggle switch. In addition to conventional dynamical cross-correlation matrix analysis, we also investigated the time-lagged correlated motions to see the persistence time of autocorrelation and cross-correlation, and to examine the causality relationships between different dynamics states of the receptor.1. Huang, N.-K.; Lin, J.-H. ….Chern Y. A new drug design targeting the adenosinergic system for Huntington's disease. PLoS. ONE 2011, 6, e20934.2. Chen, J.-B.;. ….Lin, J.-H., Fang J.-M. Design and synthesis of novel dual-action compounds targeting adenosine A2A receptor for neuroprotection. ChemMedChem 2011, 6, 1390-1400.