ArticleThe Journal of biological chemistry2013
Biased and constitutive signaling in the CC-chemokine receptor CCR5 by manipulating the interface between transmembrane helices 6 and 7.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed.
- Inhibition of constitutive activity of the atypical chemokine receptor 3 by the small-molecule inverse agonist VUF16840.Molecular pharmacology · 2025Article
- The Role of the CCR5 Receptor in Neuropathic Pain Modulation: Current Insights and Therapeutic Implications.Biomedicines · 2025Review
- Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes.The Journal of clinical endocrinology and metabolism · 2023Article
- Deciphering Evolutionary Trajectories of Lactate Dehydrogenases Provides New Insights into Allostery.Molecular biology and evolution · 2023Article
- Development of tolerance to chemokine receptor antagonists: current paradigms and the need for further investigation.Frontiers in immunology · 2023Review
- Structural basis for receptor selectivity and inverse agonism in S1PNature communications · 2022Article
- Review
- Co-receptor signaling in the pathogenesis of neuroHIV.Retrovirology · 2021Review
- Receptor-Arrestin Interactions: The GPCR Perspective.Biomolecules · 2021Review
- Novel fluorescent GPCR biosensor detects retinal equilibrium binding to opsin and active G protein and arrestin signaling conformations.The Journal of biological chemistry · 2020Article
- A Conserved Proline Hinge Mediates Helix Dynamics and Activation of Rhodopsin.Structure (London, England : 1993) · 2020Article
- Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR.Science (New York, N.Y.) · 2020Article
- Selective Allosteric Modulation of N-Terminally Cleaved, but Not Full Length CCL3 in CCR1.ACS pharmacology & translational science · 2019Article
- The impact of genetic adaptation on chimpanzee subspecies differentiation.PLoS genetics · 2019Article
- Biased Signaling of CCL21 and CCL19 Does Not Rely on N-Terminal Differences, but Markedly on the Chemokine Core Domains and Extracellular Loop 2 of CCR7.Frontiers in immunology · 2019Article
- CCR5 structural plasticity shapes HIV-1 phenotypic properties.PLoS pathogens · 2018Article
- Using accelerated molecular dynamics simulation to shed light on the mechanism of activation/deactivation upon mutations for CCR5.RSC advances · 2018Article
- Toward an understanding of the structural basis of allostery in muscarinic acetylcholine receptors.The Journal of general physiology · 2018Review
- Article
- Dynamic and Kinetic Elements of µ-Opioid Receptor Functional Selectivity.Scientific reports · 2017Article
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6 authors.
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No grant is acknowledged in the PubMed record.
Abstract
The equilibrium state of CCR5 is manipulated here toward either activation or inactivation by introduction of single amino acid substitutions in the transmembrane domains (TMs) 6 and 7. Insertion of a steric hindrance mutation in the center of TM7 (G286F in position VII:09/7.42) resulted in biased signaling. Thus, β-arrestin recruitment was eliminated, whereas constitutive activity was observed in Gαi-mediated signaling. Furthermore, the CCR5 antagonist aplaviroc was converted to a full agonist (a so-called efficacy switch). Computational modeling revealed that the position of the 7TM receptor-conserved Trp in TM6 (Trp-248 in position VI:13/6.48, part of the CWXP motif) was influenced by the G286F mutation, causing Trp-248 to change orientation away from TM7. The essential role of Trp-248 in CCR5 activation was supported by complete inactivity of W248A-CCR5 despite maintaining chemokine binding. Furthermore, replacing Trp-248 with a smaller aromatic amino acid (Tyr/Phe) impaired the β-arrestin recruitment, yet with maintained G protein activity (biased signaling); also, here aplaviroc switched to a full agonist. Thus, the altered positioning of Trp-248, induced by G286F, led to a constraint of G protein active, but β-arrestin inactive and thus biased, CCR5 conformation. These results provide important information on the molecular interplay and impact of TM6 and TM7 for CCR5 activity, which may be extrapolated to other chemokine receptors and possibly to other 7TM receptors.
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