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Molecular dynamics simulations reveal insights into key structural elements of adenosine receptors.
- Source :
-
Biochemistry [Biochemistry] 2011 May 17; Vol. 50 (19), pp. 4194-208. Date of Electronic Publication: 2011 Apr 20. - Publication Year :
- 2011
-
Abstract
- The crystal structure of the human A(2A) adenosine receptor, a member of the G protein-coupled receptor (GPCR) family, is used as a starting point for the structural characterization of the conformational equilibrium around the inactive conformation of the human A(2) (A(2A) and A(2B)) adenosine receptors (ARs). A homology model of the closely related A(2B)AR is reported, and the two receptors were simulated in their apo form through all-atom molecular dynamics (MD) simulations. Different conditions were additionally explored in the A(2A)AR, including the protonation state of crucial histidines or the presence of the cocrystallized ligand. Our simulations reveal the role of several conserved residues in the ARs in the conformational equilibrium of the receptors. The "ionic lock" absent in the crystal structure of the inactive A(2A)AR is rapidly formed in the two simulated receptors, and a complex network of interacting residues is presented that further stabilizes this structural element. Notably, the observed rotameric transition of Trp6.48 ("toggle switch"), which is thought to initiate the activation process in GPCRs, is accompanied by a concerted rotation of the conserved residue of the A(2)ARs, His6.52. This new conformation is further stabilized in the two receptors under study by a novel interaction network involving residues in transmembrane (TM) helices TM5 (Asn5.42) and TM3 (Gln3.37), which resemble the conformational changes recently observed in the agonist-bound structure of β-adrenoreceptors. Finally, the interaction between Glu1.39 and His7.43, a pair of conserved residues in the family of ARs, is found to be weaker than previously thought, and the role of this interaction in the structure and dynamics of the receptor is thoroughly examined. All these findings suggest that, despite the commonalities with other GPCRs, the conformational equilibrium of ARs is also modulated by specific residues of the family.
- Subjects :
- Amino Acid Sequence
Crystallography, X-Ray
Disulfides chemistry
Humans
Ligands
Membrane Proteins chemistry
Membrane Proteins metabolism
Models, Molecular
Protein Stability
Protein Structure, Tertiary
Receptor, Adenosine A2A metabolism
Receptor, Adenosine A2B metabolism
Sequence Homology, Amino Acid
Molecular Dynamics Simulation
Multigene Family
Receptor, Adenosine A2A chemistry
Receptor, Adenosine A2B chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4995
- Volume :
- 50
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21480628
- Full Text :
- https://doi.org/10.1021/bi200100t