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 210 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.
Highlights
G-protein coupled receptors (GPCRs) are one of the most versatile membrane proteins that mediate cellular responses to a myriad of extracellular signals associated with our perception, cardiovasicular, and immune functions [1]
By projecting the receptor dynamics on these binary switches that yield 210 microstates, we show that (i) the receptors in apo, antagonistbound, 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
To investigate the microscopic underpinnings of intramolecular signaling that regulates the activation of GPCRs, we performed molecular dynamics simulations of the PLOS Computational Biology | DOI:10.1371/journal.pcbi
Summary
G-protein coupled receptors (GPCRs) are one of the most versatile membrane proteins that mediate cellular responses to a myriad of extracellular signals associated with our perception, cardiovasicular, and immune functions [1]. Consisting of seven transmembrane (TM) helices, each of which is connected to the TM helix by either an intracellular loop (ICL) or an extracellular loop (ECL), the interior of GPCR forms an interhelical residueto-residue interaction network that can transmit the signal specific to the ligand and/or receptor subtype. Binding of an agonist to the orthosteric site leads to conformational rearrangement of TM helices, transforming the inactive conformation to the active one, which in turn enables accommodation of G-proteins and intracellular signal transductions [1, 3, 4]. Upon binding of an agonist, the microswitch residues change the orientation of their side chain, which transforms the global configuration of TM helices into the active form and helps the intracellular domain accommodate G-proteins [5]. In contast, binding of an inverse-agonist suppresses the GPCR function below the basal level, to which the apo or antagonist-bound forms of GPCRs is likely to be tuned [1]
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