Structural basis of dimerization of chemokine receptors CCR5 and CXCR4.

Daniele Di Marino, Paolo Conflitti, Stefano Motta, Vittorio Limongelli

Nature communications 2023 Oct 13

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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. © 2023. Springer Nature Limited.

Citation

Daniele Di Marino, Paolo Conflitti, Stefano Motta, Vittorio Limongelli. Structural basis of dimerization of chemokine receptors CCR5 and CXCR4. Nature communications. 2023 Oct 13;14(1):6439