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Communication over the network of binary switches regulates the activation of A2A adenosine receptor.

Lee Y, Choi S, Hyeon C - PLoS Comput. Biol. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: National Leading Research Laboratory (NLRL) of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Korea.

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 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.

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Agonist inserted to apo form.(a) Time traces from the case 1 to case 4. In the cases 1 and 2, the agonist was inserted into the apo form when the ionic-lock was intact; whereas in the cases 3 and 4, the agonist was inserted when the ionic-lock was disrupted. (b) Average values of switch from 1 to 10 for the case 1 through 4. (c) Population of microstates sampled after the insertion of agonist. (d) Hamming distance and complexity calculated for cases 1–4. (e) The stars are the locations of the cases from 1 to 4, calculated in terms of Hamming distance relative to the apo, antagonist, and agonist forms.
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pcbi.1004044.g008: Agonist inserted to apo form.(a) Time traces from the case 1 to case 4. In the cases 1 and 2, the agonist was inserted into the apo form when the ionic-lock was intact; whereas in the cases 3 and 4, the agonist was inserted when the ionic-lock was disrupted. (b) Average values of switch from 1 to 10 for the case 1 through 4. (c) Population of microstates sampled after the insertion of agonist. (d) Hamming distance and complexity calculated for cases 1–4. (e) The stars are the locations of the cases from 1 to 4, calculated in terms of Hamming distance relative to the apo, antagonist, and agonist forms.

Mentions: Effect of inserting agonist to the apo state. Anticipating a detectable conformational change from inactive to active state, we generated 4 additional time traces by inserting agonist to the orthosteric binding site in the simulation trajectories of the apo state (Fig. 8a, Fig. S9. See Methods for the details of the simulation). The first two traces (cases 1 & 2) were generated by inserting agonist at 125 ns and 150 ns when the ionic-lock was still intact (s4 = 0) and were simulated for ≈ 750 ns. The second two traces (cases 3 & 4) were generated at 595 ns and 625 ns when the ionic-lock was disrupted (s4 = 1), and were simulated for ≈ 250 ns. The consequences of the insertion of agonist, summarized in Fig. 8, is still minor, which is evident when the average value of each switch ⟨si⟩ (i = 1,…,10) is compared (Fig. 5b middle panel versus Fig. 8b). This is not so surprising given that time scale of our simulation ( < 1 μsec) is still too short to see a complete transition from inactive to active state in GPCRs, which is typically longer than milisecond time scale [48]. Although the overall trend of ⟨si⟩ looks similar, each trace from the insertion of agonist explores distinct microstate population (Fig. 8c).


Communication over the network of binary switches regulates the activation of A2A adenosine receptor.

Lee Y, Choi S, Hyeon C - PLoS Comput. Biol. (2015)

Agonist inserted to apo form.(a) Time traces from the case 1 to case 4. In the cases 1 and 2, the agonist was inserted into the apo form when the ionic-lock was intact; whereas in the cases 3 and 4, the agonist was inserted when the ionic-lock was disrupted. (b) Average values of switch from 1 to 10 for the case 1 through 4. (c) Population of microstates sampled after the insertion of agonist. (d) Hamming distance and complexity calculated for cases 1–4. (e) The stars are the locations of the cases from 1 to 4, calculated in terms of Hamming distance relative to the apo, antagonist, and agonist forms.
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getmorefigures.php?uid=PMC4322061&req=5

pcbi.1004044.g008: Agonist inserted to apo form.(a) Time traces from the case 1 to case 4. In the cases 1 and 2, the agonist was inserted into the apo form when the ionic-lock was intact; whereas in the cases 3 and 4, the agonist was inserted when the ionic-lock was disrupted. (b) Average values of switch from 1 to 10 for the case 1 through 4. (c) Population of microstates sampled after the insertion of agonist. (d) Hamming distance and complexity calculated for cases 1–4. (e) The stars are the locations of the cases from 1 to 4, calculated in terms of Hamming distance relative to the apo, antagonist, and agonist forms.
Mentions: Effect of inserting agonist to the apo state. Anticipating a detectable conformational change from inactive to active state, we generated 4 additional time traces by inserting agonist to the orthosteric binding site in the simulation trajectories of the apo state (Fig. 8a, Fig. S9. See Methods for the details of the simulation). The first two traces (cases 1 & 2) were generated by inserting agonist at 125 ns and 150 ns when the ionic-lock was still intact (s4 = 0) and were simulated for ≈ 750 ns. The second two traces (cases 3 & 4) were generated at 595 ns and 625 ns when the ionic-lock was disrupted (s4 = 1), and were simulated for ≈ 250 ns. The consequences of the insertion of agonist, summarized in Fig. 8, is still minor, which is evident when the average value of each switch ⟨si⟩ (i = 1,…,10) is compared (Fig. 5b middle panel versus Fig. 8b). This is not so surprising given that time scale of our simulation ( < 1 μsec) is still too short to see a complete transition from inactive to active state in GPCRs, which is typically longer than milisecond time scale [48]. Although the overall trend of ⟨si⟩ looks similar, each trace from the insertion of agonist explores distinct microstate population (Fig. 8c).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: National Leading Research Laboratory (NLRL) of Molecular Modeling and Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul 120-750, Korea.

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 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.

Show MeSH
Related in: MedlinePlus