Structural basis of dimerization of chemokine receptors CCR5 and CXCR4
Informazioni aggiuntive
Autori
Di Martino D.,
Conflitti P.,
Motta S.,
Limongelli V.
Tipo
Articolo pubblicato in rivista scientifica
Anno
2023
Lingua
Inglese
Sommario
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.
Parole chiave
Chemokines , Computational biophysics, Computational chemistry, G protein-coupled receptors, Molecular dynamics
Periodico
Nature communications
Volume
14
Numero ( Mese )
6439
Diffusione
Licenza
CC BY
Visibilità
Pubblico
Status open access
Gold
