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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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Cross-correlations among binary switches.(a) Cross-correlation matrices between the changes in 10 ON/OFF switches for three distinct receptor states calculated by using Fig. 3. The symbols “P” in the matrix elements are for the postive correlatin (Cij > 0.25); “N” is for the negative correlation (Cij < −0.25). (b) Diagram of the cross-correlation between the switches. TM1 to TM7 helices are displayed in gray circles, and the ten switches are specified with the boxes. The positive and negative correlations are depicted using red and blue lines, respectively. (c) Coordination of the antagonist and agonist to 7 (W246). W246 and the bound ligands are depicted in the left and right figures. The graph in the middle shows the distances between the center of mass of the W246 (indole 6-ring) and the center of mass of the furan ring (ZM-241385, blue) and ethyl group (UK-432097, red).
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pcbi.1004044.g007: Cross-correlations among binary switches.(a) Cross-correlation matrices between the changes in 10 ON/OFF switches for three distinct receptor states calculated by using Fig. 3. The symbols “P” in the matrix elements are for the postive correlatin (Cij > 0.25); “N” is for the negative correlation (Cij < −0.25). (b) Diagram of the cross-correlation between the switches. TM1 to TM7 helices are displayed in gray circles, and the ten switches are specified with the boxes. The positive and negative correlations are depicted using red and blue lines, respectively. (c) Coordination of the antagonist and agonist to 7 (W246). W246 and the bound ligands are depicted in the left and right figures. The graph in the middle shows the distances between the center of mass of the W246 (indole 6-ring) and the center of mass of the furan ring (ZM-241385, blue) and ethyl group (UK-432097, red).

Mentions: Cross-correlations of the dynamics between binary switches. To identify the correlation between the ON/OFF dynamics of binary switches, we calculated their cross-correlation (Cij) by using the conformational ensemble from the simulations.Cij=⟨δsiδsj⟩⟨(δsi)2⟩⟨(δsj)2⟩(3)where δsi = si−⟨si⟩ is the variation of the switch value from its mean. Cij assesses the extent of coherence in the “change” in switch dynamics between the i-th and j-th switches. Marked differences of the correlation pattern are observed in the three distinct receptor states (Fig. 7a): (i) The apo state (the middle panel in Fig. 7) has only one positive correlation (), and many other negative correlations (, , , ); (ii) By contrast, in the antagonist-bound state (the left panel in Fig. 7), a positive correlation (> 0.25) is detected only between the and , and the negative correlations present in the apo state are suppressed; (iii) The agonist-bound state has a greater number of the positive correlations between the switches. The diagrams in Fig. 7b illustrate how the allosteric couplings are established among the switches, especially highlighting many positive couplings among switches in the agonist-bound state. Most notably, (W246), a central rotameric switch located at the deep bottom of ligand binding cleft, displays direct couplings with 6 other switches , , , , , and , and additional positive correlations are observed in , , , . This suggests that intramolecular signaling over the entire structure can be initiated by stimulating the .


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

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

Cross-correlations among binary switches.(a) Cross-correlation matrices between the changes in 10 ON/OFF switches for three distinct receptor states calculated by using Fig. 3. The symbols “P” in the matrix elements are for the postive correlatin (Cij > 0.25); “N” is for the negative correlation (Cij < −0.25). (b) Diagram of the cross-correlation between the switches. TM1 to TM7 helices are displayed in gray circles, and the ten switches are specified with the boxes. The positive and negative correlations are depicted using red and blue lines, respectively. (c) Coordination of the antagonist and agonist to 7 (W246). W246 and the bound ligands are depicted in the left and right figures. The graph in the middle shows the distances between the center of mass of the W246 (indole 6-ring) and the center of mass of the furan ring (ZM-241385, blue) and ethyl group (UK-432097, red).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4322061&req=5

pcbi.1004044.g007: Cross-correlations among binary switches.(a) Cross-correlation matrices between the changes in 10 ON/OFF switches for three distinct receptor states calculated by using Fig. 3. The symbols “P” in the matrix elements are for the postive correlatin (Cij > 0.25); “N” is for the negative correlation (Cij < −0.25). (b) Diagram of the cross-correlation between the switches. TM1 to TM7 helices are displayed in gray circles, and the ten switches are specified with the boxes. The positive and negative correlations are depicted using red and blue lines, respectively. (c) Coordination of the antagonist and agonist to 7 (W246). W246 and the bound ligands are depicted in the left and right figures. The graph in the middle shows the distances between the center of mass of the W246 (indole 6-ring) and the center of mass of the furan ring (ZM-241385, blue) and ethyl group (UK-432097, red).
Mentions: Cross-correlations of the dynamics between binary switches. To identify the correlation between the ON/OFF dynamics of binary switches, we calculated their cross-correlation (Cij) by using the conformational ensemble from the simulations.Cij=⟨δsiδsj⟩⟨(δsi)2⟩⟨(δsj)2⟩(3)where δsi = si−⟨si⟩ is the variation of the switch value from its mean. Cij assesses the extent of coherence in the “change” in switch dynamics between the i-th and j-th switches. Marked differences of the correlation pattern are observed in the three distinct receptor states (Fig. 7a): (i) The apo state (the middle panel in Fig. 7) has only one positive correlation (), and many other negative correlations (, , , ); (ii) By contrast, in the antagonist-bound state (the left panel in Fig. 7), a positive correlation (> 0.25) is detected only between the and , and the negative correlations present in the apo state are suppressed; (iii) The agonist-bound state has a greater number of the positive correlations between the switches. The diagrams in Fig. 7b illustrate how the allosteric couplings are established among the switches, especially highlighting many positive couplings among switches in the agonist-bound state. Most notably, (W246), a central rotameric switch located at the deep bottom of ligand binding cleft, displays direct couplings with 6 other switches , , , , , and , and additional positive correlations are observed in , , , . This suggests that intramolecular signaling over the entire structure can be initiated by stimulating the .

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