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Sci Signal. 2018 May 8;11(529). pii: eaal2869. doi: 10.1126/scisignal.aal2869.

CCR5 adopts three homodimeric conformations that control cell surface delivery.

Author information

1
Institut National de la Santé et de la Recherche Médicale Unit 1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, 75015 Paris, France.
2
Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, 75015 Paris, France.
3
Institut Curie, Paris Sciences and Lettres (PSL) Research University, CNRS UMR144, 75005 Paris, France.
4
Université de Strasbourg, CNRS UMR7200, Medalis Drug Discovery Center, 67400 Illkirch, France.
5
Institut National de la Santé et de la Recherche Médicale Unit 1108, Viral Pathogenesis Unit, Department of Virology, Institut Pasteur, 75015 Paris, France. anne.brelot@pasteur.fr.

Abstract

Biophysical methods and x-ray crystallography have revealed that class A G protein-coupled receptors (GPCRs) can form homodimers. We combined computational approaches with receptor cross-linking, energy transfer, and a newly developed functional export assay to characterize the residues involved in the dimerization interfaces of the chemokine receptor CCR5, the major co-receptor for HIV-1 entry into cells. We provide evidence of three distinct CCR5 dimeric organizations, involving residues of transmembrane helix 5. Two dimeric states corresponded to unliganded receptors, whereas the binding of the inverse agonist maraviroc stabilized a third state. We found that CCR5 dimerization was required for targeting the receptor to the plasma membrane. These data suggest that dimerization contributes to the conformational diversity of inactive class A GPCRs and may provide new opportunities to investigate the cellular entry of HIV-1 and mechanisms for its inhibition.

PMID:
29739880
DOI:
10.1126/scisignal.aal2869
[Indexed for MEDLINE]

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