CCR5 adopts three homodimeric conformations that control cell surface delivery

Jin, Jun; Momboisse, Fanny; Boncompain, Gaëlle; Koensgen, Florian; Zhou, Zhicheng; Cordeiro, Nelia; Arenzana-Seisdedos, Fernando; Perez, Franck; Lagane, Bernard; Kellenberger, Esther; Brelot, Anne

doi:10.1126/scisignal.aal2869

Cited by 42 publications

(72 citation statements)

References 68 publications

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“…An additional application of the PALM imaging studies was the integration with molecular modelling approaches to identify possible LHR-LHR interfaces. Surprisingly, this suggested that multiple interfaces for distinct di/oligomers were predicted, and is consistent with the concept that these receptors form diverse physical and functional complexes in our study and more recently in work with distinct Class A GPCRs (25)(26)(27).…”

Section: Pd-palm Unveils Spatial Organization and Stoichiometry Of Gpsupporting

confidence: 92%

G Protein-Coupled Receptor Signaling

2019

Methods in Molecular Biology

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Super-resolution imaging has provided unprecedented insight in the molecular complexities of fundamental cell biological questions. For G protein-coupled receptors (GPCRs), its application to the study of receptor homomers and heteromers have unveiled the diversity of complexes these GPCRs can form at the plasma membrane at a structural and functional level. Here we describe our methodological approach of photoactivated localization microscopy with photoactivable dyes (PD-PALM) to visualize and quantify the spatial assembly of GPCR heteromers at the plasma membrane.

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Section: Pd-palm Unveils Spatial Organization and Stoichiometry Of Gpsupporting

confidence: 92%

G Protein-Coupled Receptor Signaling

2019

Methods in Molecular Biology

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“…To investigate the role of CCR5 di-/oligo-merization in gp120 binding, we compared the ligand binding properties of FLAG/SNAP-tagged wild-type (WT) and L196K CCR5. Indeed, we recently identified that Leu-196 is part of the CCR5 dimerization interface [52]. The L196K mutation results in receptor dimers that are less stable and involve alternative dimerization interfaces, as compared to WT CCR5 ([52] and Fig 3B).…”

Section: Resultsmentioning

confidence: 96%

“…Indeed, we recently identified that Leu-196 is part of the CCR5 dimerization interface [52]. The L196K mutation results in receptor dimers that are less stable and involve alternative dimerization interfaces, as compared to WT CCR5 ([52] and Fig 3B). Receptors were expressed in HEK 293 cells and membranes containing similar amounts of either WT- or L196K-CCR5 (Fig 3A) were prepared.…”

Section: Resultsmentioning

confidence: 96%

CCR5 structural plasticity shapes HIV-1 phenotypic properties

et al. 2018

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CCR5 plays immune functions and is the coreceptor for R5 HIV-1 strains. It exists in diverse conformations and oligomerization states. We interrogated the significance of the CCR5 structural diversity on HIV-1 infection. We show that envelope glycoproteins (gp120s) from different HIV-1 strains exhibit divergent binding levels to CCR5 on cell lines and primary cells, but not to CD4 or the CD4i monoclonal antibody E51. This owed to differential binding of the gp120s to different CCR5 populations, which exist in varying quantities at the cell surface and are differentially expressed between different cell types. Some, but not all, of these populations are antigenically distinct conformations of the coreceptor. The different binding levels of gp120s also correspond to differences in their capacity to bind CCR5 dimers/oligomers. Mutating the CCR5 dimerization interface changed conformation of the CCR5 homodimers and modulated differentially the binding of distinct gp120s. Env-pseudotyped viruses also use particular CCR5 conformations for entry, which may differ between different viruses and represent a subset of those binding gp120s. In particular, even if gp120s can bind both CCR5 monomers and oligomers, impairment of CCR5 oligomerization improved viral entry, suggesting that HIV-1 prefers monomers for entry. From a functional standpoint, we illustrate that the nature of the CCR5 molecules to which gp120/HIV-1 binds shapes sensitivity to inhibition by CCR5 ligands and cellular tropism. Differences exist in the CCR5 populations between T-cells and macrophages, and this is associated with differential capacity to bind gp120s and to support viral entry. In macrophages, CCR5 structural plasticity is critical for entry of blood-derived R5 isolates, which, in contrast to prototypical M-tropic strains from brain tissues, cannot benefit from enhanced affinity for CD4. Collectively, our results support a role for CCR5 heterogeneity in diversifying the phenotypic properties of HIV-1 isolates and provide new clues for development of CCR5-targeting drugs.

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“…Crystal structures have provided a relevant guide toward the rational design of such mutations in strategic positions. This strategy has proven effective to map the CCR5 dimeric interface, where disulphide crosslinking experiments based on the dimeric interfaces observed in the CXCR4 and m-opioid receptor crystal structures (Jin et al, 2018).…”

Section: Lessons From Chemokine Receptor X-ray Structuresmentioning

confidence: 99%

Chemokine Receptor Crystal Structures: What Can Be Learned from Them?

Arimont

Hoffmann

Graaf

et al. 2019

Molecular Pharmacology

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Chemokine receptors belong to the class A of G protein-coupled receptors (GPCRs) and are implicated in a wide variety of physiologic functions, mostly related to the homeostasis of the immune system. Chemokine receptors are also involved in multiple pathologic processes, including immune and autoimmune diseases, as well as cancer. Hence, several members of this GPCR subfamily are considered to be very relevant therapeutic targets. Since drug discovery efforts can be significantly reinforced by the availability of crystal structures, substantial efforts in the area of chemokine receptor structural biology could dramatically increase the outcome of drug discovery campaigns. This short review summarizes the available data on chemokine receptor crystal structures, discusses the numerous applications from chemokine receptor structures that can enhance the daily work of molecular pharmacologists, and describes the challenges and pitfalls to consider when relying on crystal structures for further research applications. SIGNIFICANCE STATEMENT This short review summarizes the available data on chemokine receptor crystal structures, discusses the numerous applications from chemokine receptor structures that can enhance the daily work of molecular pharmacologists, and describes the challenges and pitfalls to consider when relying on crystal structures for further research applications.

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CCR5 adopts three homodimeric conformations that control cell surface delivery

Cited by 42 publications

References 68 publications

G Protein-Coupled Receptor Signaling

G Protein-Coupled Receptor Signaling

CCR5 structural plasticity shapes HIV-1 phenotypic properties

Chemokine Receptor Crystal Structures: What Can Be Learned from Them?

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