CCR5 Conformations Are Dynamic and Modulated by Localization, Trafficking and G Protein Association

Flegler, Ayanna; Cianci, Gianguido C.; Hope, Thomas J.

doi:10.1371/journal.pone.0089056

Cited by 29 publications

(45 citation statements)

References 50 publications

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“…Structural studies of  2 adrenergic receptor interacting with G protein has confirmed the paradigm that a receptor must be bound to a transducer to stabilize the agonist-receptor interaction (32). Likewise, the conformation of CCR5 molecules on the cellular surface is altered upon PTX-induced abrogation of G i/o precoupling (33). Similar to our results, other reports have also described incomplete inhibition of CCR5-mediated Ca 2+ flux by PTX, suggesting that G i/o plays a role in agonist binding but not in Ca 2+ flux (34)(35)(36).…”

Section: Discussionmentioning

confidence: 94%

G protein subtype–specific signaling bias in a series of CCR5 chemokine analogs

et al. 2018

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Chemokines and some chemical analogs of chemokines prevent cellular HIV-1 entry when bound to the HIV-1 coreceptors C-C chemokine receptor 5 (CCR5) or C-X-C chemokine receptor 4 (CXCR4), which are G protein–coupled receptors (GPCRs). The ideal HIV-1 entry blocker targeting the coreceptors would display ligand bias and avoid activating G protein–mediated pathways that lead to inflammation. We compared CCR5-dependent activation of second messenger pathways in a single cell line. We studied two endogenous chemokines [RANTES (also known as CCL5) and MIP-1α (also known as CCL3)] and four chemokine analogs of RANTES (5P12-, 5P14-, 6P4-, and PSC-RANTES). We found that CCR5 signaled through both Gi/o and Gq/11. IP1 accumulation and Ca2+ flux arose from Gq/11 activation, rather than from Gβγ subunit release after Gi/o activation as had been previously proposed. The 6P4- and PSC-RANTES analogs were superagonists for Gq/11 activation, whereas the 5P12- and 5P14-RANTES analogs displayed a signaling bias for Gi/o. These results demonstrate that RANTES analogs elicit G protein subtype–specific signaling bias and can cause CCR5 to couple preferentially to Gq/11 rather than to Gi/o signaling pathways. We propose that G protein subtype–specific signaling bias may be a general feature of GPCRs that can couple to more than one G protein family.

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Section: Discussionmentioning

confidence: 94%

G protein subtype–specific signaling bias in a series of CCR5 chemokine analogs

et al. 2018

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“…This tool provides a powerful method to characterize viral entry efficiency as a function of CD4 and CCR5 expression levels [50]. These affinofile cell lines also permitted to demonstrate that several CCR5 conformations (distinguished thanks to specific monoclonal antibodies), exhibiting different localization and G-protein association, might have implications in selective targeting of HIV-1 [51]. This system is also used in our lab to check whether the expression level of receptors and co-receptors can impact the dynamic of each other and the infection efficiency of various virus strains.…”

Section: Cxcr4 Co-receptormentioning

confidence: 99%

Membrane organization of virus and target cell plays a role in HIV entry

2014

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The initial steps of the Human Immunodeficiency Virus (HIV) replication cycle play a crucial role that arbitrates viral tropism and infection efficiency. Before the release of its genome into the host cell cytoplasm, viruses operate a complex sequence of events that take place at the plasma membrane of the target cell. The first step is the binding of the HIV protein envelope (Env) to the cellular receptor CD4. This triggers conformational changes of the gp120 viral protein that allow its interaction with a co-receptor that can be either CCR5 or CXCR4, defining the tropism of the virus entering the cell. This sequential interaction finally drives the fusion of the viral and host cell membrane or to the endocytosis of the viruses. Here, we discuss how the membrane composition and organization of both the virus and the target cell can affect these steps and thus influence the capability of the viruses to infect cells.

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“…Besides, CCR5 also involves in many autoimmune diseases, such as organ transplant rejection [1], diabetes [2], and rheumatoid arthritis [3]. Recent studies also indicated that CCR5 is crucial for both HIV-1 infection [4,5] and different kinds of cancer progressions [6]. During HIV-1 infection, two immune cell surface proteins, cluster of differentiation 4 (CD4) and CCR5, are most commonly adopted for entering host cells [7].…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Pharmacophore Modeling to Discover Novel CCR5 Inhibitors for HIV-1/Cancers Therapy

Lin

Ho²,

Liu

2019

JBiSE

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CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), not only plays a significant role in inflammatory responses, but also correlates with HIV-1 infection and cancer progression. Recently, blocking of CCR5 has been considered as an effective strategy in HIV-1/cancers therapy. So far, only Maraviroc has been approved by FDA in 2007, while the other CCR5 inhibitors have failed in their clinical trials. In this study, a highly selective structure-based pharmacophore model was constructed, validated, and applied for virtual screening to retrieve novel CCR5 inhibitors from NCI database. Finally, one potential CCR5 inhibitor candidate, NSC13165, was identified after molecular docking, molecular dynamics (MD) simulations, binding free energy analyses and ADMET prediction. Docking and MD simulation results not only suggested that NSC13165 reserves the common binding mode of the most known CCR5 inhibitors, but also provided important insights toward the allosteric inhibition mechanism of CCR5. The results of binding free energy analyses indicated that the binding affinity of NSC13165 is much better than that of Maraviroc and that van der Waals interaction is the key driving force during the binding process. ADMET prediction suggested that NSC13165 exhibits very low risk of causing lethal side effects. Altogether, our results strongly suggest that NSC13165 has great potential to serve as a novel CCR5 inhibitor, which may be further tested in vitro/in vivo as a drug target for HIV-1/cancers therapy or be used as a lead compound for improving its efficacy through chemical modifications.

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CCR5 Conformations Are Dynamic and Modulated by Localization, Trafficking and G Protein Association

Cited by 29 publications

References 50 publications

G protein subtype–specific signaling bias in a series of CCR5 chemokine analogs

G protein subtype–specific signaling bias in a series of CCR5 chemokine analogs

Membrane organization of virus and target cell plays a role in HIV entry

Structure-Based Pharmacophore Modeling to Discover Novel CCR5 Inhibitors for HIV-1/Cancers Therapy

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