Investigating allosteric effects on the functional dynamics of beta 2-adrenergic ternary complexes with enhanced-sampling simulations

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autor(en): Saleh N, Saladino G, Gervasio FL, Clark T
Zeitschrift: Chemical Science
Verlag: ROYAL SOC CHEMISTRY
Jahr der Veröffentlichung: 2017
Band: 8
Heftnummer: 5
Seitenbereich: 4019-4026
ISSN: 2041-6520


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 beta-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 beta-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 beta-arrestin- and G(s)-complexes with the beta 2-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.


FAU-Autoren / FAU-Herausgeber

Clark, Timothy apl. Prof. Dr.
Computer-Chemie-Centrum
Saleh, Noureldin
Computer-Chemie-Centrum


Autor(en) der externen Einrichtung(en)
University College London (UCL) (University of London)


Zitierweisen

APA:
Saleh, N., Saladino, G., Gervasio, F.L., & Clark, T. (2017). Investigating allosteric effects on the functional dynamics of beta 2-adrenergic ternary complexes with enhanced-sampling simulations. Chemical Science, 8(5), 4019-4026. https://dx.doi.org/10.1039/c6sc04647a

MLA:
Saleh, Noureldin, et al. "Investigating allosteric effects on the functional dynamics of beta 2-adrenergic ternary complexes with enhanced-sampling simulations." Chemical Science 8.5 (2017): 4019-4026.

BibTeX: 

Zuletzt aktualisiert 2018-17-12 um 23:08