Characterizing CCR2 Homodimers Using Homology-derived and AI-predicted Interfaces
Abstract
Deciphering the functional roles of G protein-coupled receptors (GPCRs) oligomers requires defining their structural organization, which remains a challenge due to the inherent flexibility of their 7 transmembrane (TM) domains. Here, we focused on determining homodimer interfaces of the chemokine receptor CCR2, a major component of the inflammatory response, for which no antagonist has yet been approved. We generated models of CCR2 homodimers combining homology modeling, a conventional in silico approach, or an AI-based AlphaFold-Multimer predictions, with molecular dynamics simulations. We determined the biological relevance of our predicted models by in cellulo cross-linking experiments, introducing a cysteine in each predicted interface. This in cellulo assay supported the homology modeling predictions, but not those predicted by AlphaFold-Multimer, and demonstrated that CCR2 forms homodimers by at least two different interfaces involving the transmembrane domains TM5 (I 5 ) or TM5 and TM6 (I 56 ). This structural arrangement of the CCR2 homodimer represents a valuable model for further studies on the functional consequences of dimerization and for the rational design of CCR2-selective drugs.
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BibTeX
@article{urvas2026characterizing,
title = {{Characterizing CCR2 Homodimers Using Homology-derived and AI-predicted Interfaces}},
author = {Lauri Urvas and Amaia Nuñez-Delmoral and Célien Jacquemard and Margaux Bilay and Jost Enninga and Anne Brelot and Esther Kellenberger},
journal = {Journal of Molecular Biology},
year = {2026},
month = nov,
doi = {10.1016/j.jmb.2026.170013},
url = {https://pasteur.hal.science/pasteur-05856390v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Characterizing CCR2 Homodimers Using Homology-derived and AI-predicted Interfaces
AU - Lauri Urvas
AU - Amaia Nuñez-Delmoral
AU - Célien Jacquemard
AU - Margaux Bilay
AU - Jost Enninga
AU - Anne Brelot
AU - Esther Kellenberger
PY - 2026
DA - 2026/11/08
JO - Journal of Molecular Biology
DO - 10.1016/j.jmb.2026.170013
UR - https://pasteur.hal.science/pasteur-05856390v1
AB - Deciphering the functional roles of G protein-coupled receptors (GPCRs) oligomers requires defining their structural organization, which remains a challenge due to the inherent flexibility of their 7 transmembrane (TM) domains. Here, we focused on determining homodimer interfaces of the chemokine receptor CCR2, a major component of the inflammatory response, for which no antagonist has yet been approved. We generated models of CCR2 homodimers combining homology modeling, a conventional in silico approach, or an AI-based AlphaFold-Multimer predictions, with molecular dynamics simulations. We determined the biological relevance of our predicted models by in cellulo cross-linking experiments, introducing a cysteine in each predicted interface. This in cellulo assay supported the homology modeling predictions, but not those predicted by AlphaFold-Multimer, and demonstrated that CCR2 forms homodimers by at least two different interfaces involving the transmembrane domains TM5 (I 5 ) or TM5 and TM6 (I 56 ). This structural arrangement of the CCR2 homodimer represents a valuable model for further studies on the functional consequences of dimerization and for the rational design of CCR2-selective drugs.
SN - 0022-2836
SN - 1089-8638
ER -