Structural basis of dimerization of chemokine receptors CCR5 and CXCR4.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 10 2023
13 10 2023
Historique:
received:
10
10
2021
accepted:
28
09
2023
medline:
23
10
2023
pubmed:
14
10
2023
entrez:
13
10
2023
Statut:
epublish
Résumé
G protein-coupled receptors (GPCRs) are prominent drug targets responsible for extracellular-to-intracellular signal transduction. GPCRs can form functional dimers that have been poorly characterized so far. Here, we show the dimerization mechanism of the chemokine receptors CCR5 and CXCR4 by means of an advanced free-energy technique named coarse-grained metadynamics. Our results reproduce binding events between the GPCRs occurring in the minute timescale, revealing a symmetric and an asymmetric dimeric structure for each of the three investigated systems, CCR5/CCR5, CXCR4/CXCR4, and CCR5/CXCR4. The transmembrane helices TM4-TM5 and TM6-TM7 are the preferred binding interfaces for CCR5 and CXCR4, respectively. The identified dimeric states differ in the access to the binding sites of the ligand and G protein, indicating that dimerization may represent a fine allosteric mechanism to regulate receptor activity. Our study offers structural basis for the design of ligands able to modulate the formation of CCR5 and CXCR4 dimers and in turn their activity, with therapeutic potential against HIV, cancer, and immune-inflammatory diseases.
Identifiants
pubmed: 37833254
doi: 10.1038/s41467-023-42082-z
pii: 10.1038/s41467-023-42082-z
pmc: PMC10575954
doi:
Substances chimiques
Receptors, G-Protein-Coupled
0
Receptors, Chemokine
0
Receptors, CCR5
0
Receptors, CXCR4
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6439Subventions
Organisme : European Research Council
ID : 101001784
Pays : International
Informations de copyright
© 2023. Springer Nature Limited.
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