Research ArticleGPCR SIGNALING

CCR5 adopts three homodimeric conformations that control cell surface delivery

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Science Signaling  08 May 2018:
Vol. 11, Issue 529, eaal2869
DOI: 10.1126/scisignal.aal2869

CCR5 delivery to the cell surface

The chemokine receptor CCR5 is a class A GPCR and co-receptor for HIV-1 infection. How class A GPCRs dimerize and how it affects their function are unclear. Jin et al. analyzed the structures of related receptors and identified CCR5 residues that mediated homodimerization. Cross-linking and energy transfer experiments and monitoring the release of receptors from the endoplasmic reticulum identified two dimeric CCR5 conformations that directed its delivery to the plasma membrane. A third CCR5 homodimer was stabilized by maraviroc, a clinically used inhibitor that binds to CCR5 and inhibits its interaction with HIV-1. These data increase our understanding of class A GPCR dimerization and provide insight into the mechanisms of inhibiting HIV-1 entry.


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.

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