ArticleBritish journal of pharmacology2010
A common intracellular allosteric binding site for antagonists of the CXCR2 receptor.
Article in British journal of pharmacology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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Who cites it
39 citing papers in PubMed, 1 synthesis or guideline pooled it, 88 citations in OpenAlex.
- Rare and low-frequency coding variants in CXCR2 and other genes are associated with hematological traits.Nature genetics · 2014Pooled it
- Biased antagonism of a series of bicyclic CXCR2 intracellular allosteric modulators.Frontiers in pharmacology · 2025Article
- Structural basis for CCR6 modulation by allosteric antagonists.Nature communications · 2024Article
- Know your molecule: pharmacological characterization of drug candidates to enhance efficacy and reduce late-stage attrition.Nature reviews. Drug discovery · 2024Review
- Molecular determinants of antagonist interactions with chemokine receptors CCR2 and CCR5.bioRxiv : the preprint server for biology · 2024Article
- Systematic assessment of chemokine ligand bias at the human chemokine receptor CXCR2 indicates G protein bias over β-arrestin recruitment and receptor internalization.Cell communication and signaling : CCS · 2024Article
- Design, Synthesis, and Application of Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the CXC Chemokine Receptor 2.Journal of medicinal chemistry · 2023Article
- Identification of a Salt Bridge That Is Functionally Important for Chemokine Receptor CXCR1 but not CXCR2.ACS pharmacology & translational science · 2023Article
- Fluorescent Ligands Enable Target Engagement Studies for the Intracellular Allosteric Binding Site of the Chemokine Receptor CXCR2.Journal of medicinal chemistry · 2023Article
- 30th Annual GPPharmaceuticals (Basel, Switzerland) · 2023Article
- Small Molecule Tools to Study Cellular Target Engagement for the Intracellular Allosteric Binding Site of GPCRs.Chemistry (Weinheim an der Bergstrasse, Germany) · 2023Article
- Review
- Article
- Synthesis and Pharmacological Evaluation of Triazolopyrimidinone Derivatives as Noncompetitive, Intracellular Antagonists for CC Chemokine Receptors 2 and 5.Journal of medicinal chemistry · 2019Article
- Potent HIV-1 protease inhibitors incorporating squaramide-derived P2 ligands: Design, synthesis, and biological evaluation.Bioorganic & medicinal chemistry letters · 2019Article
- Activation of CXCL5-CXCR2 axis promotes proliferation and accelerates G1 to S phase transition of papillary thyroid carcinoma cells and activates JNK and p38 pathways.Cancer biology & therapy · 2019Article
- Emerging Paradigm of Intracellular Targeting of G Protein-Coupled Receptors.Trends in biochemical sciences · 2018Review
- Intracellular Receptor Modulation: Novel Approach to Target GPCRs.Trends in pharmacological sciences · 2018Review
- Bicyclo[2.2.1]heptane containingRSC advances · 2018Article
- Effect of CXCR2 Inhibition on Behavioral Outcomes and Pathology in Rat Model of Neuromyelitis Optica.Journal of immunology research · 2018Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeWe have previously shown that SB265610 (1-(2-bromo-phenyl)-3-(7-cyano-3H-benzotriazol-4-yl)-urea) behaves as an allosteric, inverse agonist at the C-X-C chemokine (CXCR)2 receptor. The aim of this study was to determine whether SB265610, in addition to two other known antagonists, bind to either of the two putative, topographically distinct, allosteric binding sites previously reported in the Literature. EXPERIMENTAL APPROACH: Ten single point mutations were introduced into the CXCR2 receptor using site-directed mutagenesis. Three CXCR2 antagonists were investigated, SB265610, Pteridone-1 (2-(2,3 difluoro-benzylsulphanyl)-4-((R)-2-hydroxy-1-methyl-ethylamino)-8H-pteridin-7-one) and Sch527123 (2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1enylamino}-benzamide), and the effect of these mutations on their binding affinity and ability to inhibit interleukin-8-stimulated binding of [(35)S]GTPgammaS was examined. KEY
resultsSeven of the nine mutations introduced into the C-terminal domain and intracellular loops of the receptor produced a significant reduction in affinity at least one of the antagonists tested. Of those seven mutations, three produced a significant reduction in the affinity of all three antagonists, namely K320A, Y314A and D84N. In all but one mutation, the changes observed on antagonist affinity were matched with effects on inhibition of interleukin-8-stimulated [(35)S]GTPgammaS binding. CONCLUSIONS AND IMPLICATIONS: These antagonists bind to a common intracellular, allosteric, binding site of the CXCR2 receptor, which has been further delineated. As many of these mutations are close to the site of G protein coupling or to a region of the receptor that is responsible for the transduction of the activation signal, our results suggest a molecular mechanism for the inhibition of receptor activation.
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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.