Structural basis of dimerization of chemokine receptors CCR5 and CXCR4
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Di Martino, Daniele
Department of Life and Environmental Sciences - New York-Marche Structural Biology Centre (NY-MaSBiC), Polytechnic University of Marche, Ancona, Italy - Neuronal Death and Neuroprotection Unit, Department of Neuroscience, Mario Negri Institute for Pharmacological Research-IRCCS, Milan, Italy - National Biodiversity Future Center (NBFC), Palermo, Italy
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Conflitti, Paolo
ORCID
Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Motta, Stefano
ORCID
Department of Earth and Environmental Sciences, University of Milano-Bicocca, Milan, Italy
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Limongelli, Vittorio
ORCID
Euler Institute (EUL), Università della Svizzera italiana, Switzerland
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Published in:
- Nature communications. - 2023, vol. 14, no. 6439
English
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.
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Chemistry
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CC BY
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gold
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https://n2t.net/ark:/12658/srd1328291
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