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Communication over the Network of Binary Switches Regulates the Activation of A(2A) Adenosine Receptor

Title
Communication over the Network of Binary Switches Regulates the Activation of A(2A) Adenosine Receptor
Authors
Lee, YoonjiChoi, SunHyeon, Changbong
Ewha Authors
최선
SCOPUS Author ID
최선scopus
Issue Date
2015
Journal Title
PLOS COMPUTATIONAL BIOLOGY
ISSN
1553-734XJCR Link1553-7358JCR Link
Citation
vol. 11, no. 2
Publisher
PUBLIC LIBRARY SCIENCE
Indexed
SCIE; SCOPUS WOS scopus
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 similar to 5 mu sec molecular dynamics simulations of A(2A) adenosine receptor (A(2A)AR) 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.
DOI
10.1371/journal.pcbi.1004044
Appears in Collections:
약학대학 > 약학과 > Journal papers
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