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Open Access Publications from the University of California

Investigation of the conformational dynamics of the apo A2Aadenosine receptor

  • Author(s): Caliman, AD
  • Swift, SE
  • Wang, Y
  • Miao, Y
  • McCammon, JA
  • et al.

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© 2015 The Protein Society. The activation/deactivation processes for G-protein coupled receptors (GPCRs) have been computationally studied for several different classes, including rhodopsin, the β2 adrenergic receptor, and the M2 muscarinic receptor. Despite determined cocrystal structures of the adenosine A2Areceptor (A2AAR) in complex with antagonists, agonists and an antibody, the deactivation process of this GPCR is not completely understood. In this study, we investigate the convergence of two apo simulations, one starting with an agonist-bound conformation (PDB: 3QAK)14and the other starting with an antagonist-bound conformation (PDB: 3EML)11. Despite the two simulations not completely converging, we were able to identify distinct intermediate steps of the deactivation process characterized by the movement of Y2887.53in the NPxxY motif. We find that Y2887.53contributes to the process by forming hydrogen bonds to residues in transmembrane helices 2 and 7 and losing these interactions upon full deactivation. Y1975.58also plays a role in the process by forming a hydrogen bond only once the side chain moves from the lipid interface to the middle of the helical bundle.

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