A structural basis for how ligand binding site changes can allosterically regulate GPCR signaling and engender functional selectivity.
Sci Signal
; 13(617)2020 02 04.
Article
em En
| MEDLINE
| ID: mdl-32019899
ABSTRACT
Signaling bias is the propensity for some agonists to preferentially stimulate G protein-coupled receptor (GPCR) signaling through one intracellular pathway versus another. We previously identified a G protein-biased agonist of the D2 dopamine receptor (D2R) that results in impaired ß-arrestin recruitment. This signaling bias was predicted to arise from unique interactions of the ligand with a hydrophobic pocket at the interface of the second extracellular loop and fifth transmembrane segment of the D2R. Here, we showed that residue Phe189 within this pocket (position 5.38 using Ballesteros-Weinstein numbering) functions as a microswitch for regulating receptor interactions with ß-arrestin. This residue is relatively conserved among class A GPCRs, and analogous mutations within other GPCRs similarly impaired ß-arrestin recruitment while maintaining G protein signaling. To investigate the mechanism of this signaling bias, we used an active-state structure of the ß2-adrenergic receptor (ß2R) to build ß2R-WT and ß2R-Y1995.38A models in complex with the full ß2R agonist BI-167107 for molecular dynamics simulations. These analyses identified conformational rearrangements in ß2R-Y1995.38A that propagated from the extracellular ligand binding site to the intracellular surface, resulting in a modified orientation of the second intracellular loop in ß2R-Y1995.38A, which is predicted to affect its interactions with ß-arrestin. Our findings provide a structural basis for how ligand binding site alterations can allosterically affect GPCR-transducer interactions and result in biased signaling.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Receptores Adrenérgicos beta 2
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Receptores Acoplados a Proteínas G
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Simulação de Dinâmica Molecular
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Beta-Arrestinas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Sci Signal
Assunto da revista:
CIENCIA
/
FISIOLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos