Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor.
Allosteric Regulation
Cell Line
Cell Membrane
/ metabolism
Fingolimod Hydrochloride
/ chemistry
Humans
Kinetics
Models, Molecular
Phosphorylation
Proprotein Convertases
/ chemistry
Protein Binding
Protein Conformation
Protein Multimerization
Protein Transport
Receptors, G-Protein-Coupled
/ agonists
Serine Endopeptidases
/ chemistry
Signal Transduction
Structure-Activity Relationship
beta-Arrestins
/ chemistry
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
15 01 2020
15 01 2020
Historique:
received:
22
03
2019
accepted:
17
12
2019
entrez:
17
1
2020
pubmed:
17
1
2020
medline:
11
5
2021
Statut:
epublish
Résumé
The structural plasticity of G-protein coupled receptors (GPCRs) enables the long-range transmission of conformational changes induced by specific orthosteric site ligands and other pleiotropic factors. Here, we demonstrate that the ligand binding cavity in the sphingosine 1-phosphate receptor S1PR1, a class A GPCR, is in allosteric communication with both the β-arrestin-binding C-terminal tail, and a receptor surface involved in oligomerization. We show that S1PR1 oligomers are required for full response to different agonists and ligand-specific association with arrestins, dictating the downstream signalling kinetics. We reveal that the active form of the immunomodulatory drug fingolimod, FTY720-P, selectively harnesses both these intramolecular networks to efficiently recruit β-arrestins in a stable interaction with the receptor, promoting deep S1PR1 internalization and simultaneously abrogating ERK1/2 phosphorylation. Our results define a molecular basis for the efficacy of fingolimod for people with multiple sclerosis, and attest that GPCR signalling can be further fine-tuned by the oligomeric state.
Identifiants
pubmed: 31941999
doi: 10.1038/s42003-020-0752-4
pii: 10.1038/s42003-020-0752-4
pmc: PMC6962373
doi:
Substances chimiques
Receptors, G-Protein-Coupled
0
beta-Arrestins
0
Proprotein Convertases
EC 3.4.21.-
Serine Endopeptidases
EC 3.4.21.-
membrane-bound transcription factor peptidase, site 1
EC 3.4.21.112
Fingolimod Hydrochloride
G926EC510T
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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