ArticleProceedings of the National Academy of Sciences of the United States of America2013
Pepducin targeting the C-X-C chemokine receptor type 4 acts as a biased agonist favoring activation of the inhibitory G protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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Who cites it
82 citing papers in PubMed, 180 citations in OpenAlex.
- Agonist-specific conformational dynamics at the βBritish journal of pharmacology · 2026Article
- A neurotensin receptor type 1-derived pepducin acts as a biased allosteric modulator to regulate target receptor function.Acta pharmaceutica Sinica. B · 2026Article
- Free fatty acid receptor 2 allosterism is defined by cellular context.Cell communication and signaling : CCS · 2026Article
- Structural Perspectives on Biased Allostery of GPCR Signaling.Handbook of experimental pharmacology · 2026Review
- Decoding ADGRE5: How Proteolytic Cleavage and Mechanical Forces Unleash Cellular Signals.Cells · 2025Article
- Multiple intramolecular triggers converge to preferential G protein coupling in the CBNature communications · 2025Article
- CXC Chemokine Ligand 12 Facilitates Gi Protein Binding to CXC Chemokine Receptor 4 by Stabilizing Packing of the Proline-Isoleucine-Phenylalanine Motif: Insights from Automated Path Searching.Journal of the American Chemical Society · 2025Article
- Altered O-glycosylation of βThe FEBS journal · 2025Article
- Endosomal chemokine receptor signalosomes regulate central mechanisms underlying cell migration.eLife · 2025Article
- Intracellular GPCR modulators enable precision pharmacology.npj drug discovery · 2025Review
- Exploring the Chemical Features and Biomedical Relevance of Cell-Penetrating Peptides.International journal of molecular sciences · 2024Review
- Essential strategies for the detection of constitutive and ligand-dependent Gi-directed activity of 7TM receptors using bioluminescence resonance energy transfer.bioRxiv : the preprint server for biology · 2024Article
- Biased activation of the vasopressin V2 receptor probed by molecular dynamics simulations, NMR and pharmacological studies.Computational and structural biotechnology journal · 2024Article
- G protein selectivity profile of GPR56/ADGRG1 and its effect on downstream effectors.Research square · 2024Article
- G protein selectivity profile of GPR56/ADGRG1 and its effect on downstream effectors.Cellular and molecular life sciences : CMLS · 2024Article
- Exploring an Intracellular Allosteric Site of CC-Chemokine Receptor 4 from 3D Models, Probe Simulations, and Mutagenesis.ACS pharmacology & translational science · 2024Article
- The novel adrenergic agonist ATR-127 targets skeletal muscle and brown adipose tissue to tackle diabesity and steatohepatitis.Molecular metabolism · 2024Article
- Discovery of a CCR2-targeting pepducin therapy for chronic pain.Pharmacological research · 2024Article
- Identification of common mechanisms and biomarkers for dermatomyositis and atherosclerosis based on bioinformatics analysis.Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI) · 2024Article
- Heterogeneous phenotype of a Chinese Familial WHIM syndrome with CXCR4Frontiers in immunology · 2024Article
22 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Short lipidated peptide sequences derived from various intracellular loop regions of G protein-coupled receptors (GPCRs) are named pepducins and act as allosteric modulators of a number of GPCRs. Recently, a pepducin selectively targeting the C-X-C chemokine receptor type 4 (CXCR4) was found to be an allosteric agonist, active in both cell-based assays and in vivo. However, the precise mechanism of action of this class of ligands remains poorly understood. In particular, given the diversity of signaling effectors that can be engaged by a given receptor, it is not clear whether pepducins can show biased signaling leading to functional selectivity. To explore the ligand-biased potential of pepducins, we assessed the effect of the CXCR4 selective pepducin, ATI-2341, on the ability of the receptor to engage the inhibitory G proteins (Gi1, Gi2 and Gi3), G13, and β-arrestins. Using bioluminescence resonance energy transfer-based biosensors, we found that, in contrast to the natural CXCR4 ligand, stromal cell-derived factor-1α, which promotes the engagement of the three Gi subtypes, G13 and the two β-arrestins, ATI-2341 leads to the engagement of the Gi subtypes but not G13 or the β-arrestins. Calculation of the transduction ratio for each pathway revealed a strong negative bias of ATI-2341 toward G13 and β-arrestins, revealing functional selectivity for the Gi pathways. The negative bias toward β-arrestins results from the reduced ability of the pepducin to promote GPCR kinase-mediated phosphorylation of the receptor. In addition to revealing ligand-biased signaling of pepducins, these findings shed some light on the mechanism of action of a unique class of allosteric regulators.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.