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Structural basis of dimerization of chemokine receptors CCR5 and CXCR4

Author

Listed:
  • Daniele Di Marino

    (Polytechnic University of Marche
    Mario Negri Institute for Pharmacological Research-IRCCS
    National Biodiversity Future Center (NBFC))

  • Paolo Conflitti

    (Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Euler Institute)

  • Stefano Motta

    (University of Milano-Bicocca)

  • Vittorio Limongelli

    (Università della Svizzera italiana (USI), Faculty of Biomedical Sciences, Euler Institute)

Abstract

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.

Suggested Citation

  • Daniele Di Marino & Paolo Conflitti & Stefano Motta & Vittorio Limongelli, 2023. "Structural basis of dimerization of chemokine receptors CCR5 and CXCR4," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42082-z
    DOI: 10.1038/s41467-023-42082-z
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    2. Peng Zhou & Taka A. Tsunoyama & Rinshi S. Kasai & Koichiro M. Hirosawa & Ziya Kalay & Amine Aladag & Takahiro K. Fujiwara & Tatsushi Yokoyama & Masayuki Sakamoto & Ryoji Kise & Masataka Yanagawa & Asu, 2025. "Single-molecule methods for characterizing receptor dimers reveal metastable opioid receptor homodimers that induce functional modulation," Nature Communications, Nature, vol. 16(1), pages 1-23, December.

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