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Investigating allosteric effects on the functional dynamics of β2-adrenergic ternary complexes with enhanced-sampling simulations

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Abstract

Signalling by G-protein coupled receptors usually occurs via ternary complexes formed under cooperative binding between the receptor, a ligand and an intracellular binding partner (a G-protein or β-arrestin). While a global rational for allosteric effects in ternary complexes would be of great help in designing ligands with specific effects, the paucity of structural data for ternary complexes with β-arrestin, together with the intrinsic difficulty of characterizing the dynamics involved in the allosteric coupling, have hindered the efforts to devise such a model. Here we have used enhanced-sampling atomistic molecular-dynamics simulations to investigate the dynamics and complex formation mechanisms of both β-arrestin- and Gs-complexes with the β2-adrenergic receptor (ADRB2) in its apo-form and in the presence of four small ligands that exert different allosteric effects. Our results suggest that the structure and dynamics of arrestin–ADRB2 complexes depend strongly on the nature of the small ligands. The complexes exhibit a variety of different coupling orientations in terms of the depth of the finger loop in the receptor and activation states of ADRB2. The simulations also allow us to characterize the cooperativity between the ligand and intracellular binding partner (IBP). Based on the complete and consistent results, we propose an experimentally testable extended ternary complex model, where direction of the cooperative effect between ligand and IBP (positive or negative) and its magnitude are predicted to be a characteristic of the ligand signaling bias. This paves the avenue to the rational design of ligands with specific functional effects.

Graphical abstract: Investigating allosteric effects on the functional dynamics of β2-adrenergic ternary complexes with enhanced-sampling simulations

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Publication details

The article was received on 17 Oct 2016, accepted on 24 Mar 2017 and first published on 24 Mar 2017


Article type: Edge Article
DOI: 10.1039/C6SC04647A
Citation: Chem. Sci., 2017, Advance Article
  • Open access: Creative Commons BY-NC license
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    Investigating allosteric effects on the functional dynamics of β2-adrenergic ternary complexes with enhanced-sampling simulations

    N. Saleh, G. Saladino, F. L. Gervasio and T. Clark, Chem. Sci., 2017, Advance Article , DOI: 10.1039/C6SC04647A

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