• Media type: E-Article
  • Title: Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: Prevention of reperfusion injury
  • Contributor: Bertini, Riccardo; Allegretti, Marcello; Bizzarri, Cinzia; Moriconi, Alessio; Locati, Massimo; Zampella, Giuseppe; Cervellera, Maria N.; Di Cioccio, Vito; Cesta, Maria C.; Galliera, Emanuela; Martinez, Fernando O.; Di Bitondo, Rosa; Troiani, Giulia; Sabbatini, Vilma; D'Anniballe, Gaetano; Anacardio, Roberto; Cutrin, Juan C.; Cavalieri, Barbara; Mainiero, Fabrizio; Strippoli, Raffaele; Villa, Pia; Di Girolamo, Maria; Martin, Franck; Gentile, Marco; [...]
  • Published: Proceedings of the National Academy of Sciences, 2004
  • Published in: Proceedings of the National Academy of Sciences
  • Extent: 11791-11796
  • Language: English
  • DOI: 10.1073/pnas.0402090101
  • ISSN: 0027-8424; 1091-6490
  • Keywords: Multidisciplinary
  • Abstract: <jats:p>The chemokine CXC ligand 8 (CXCL8)/IL-8 and related agonists recruit and activate polymorphonuclear cells by binding the CXC chemokine receptor 1 (CXCR1) and CXCR2. Here we characterize the unique mode of action of a small-molecule inhibitor (Repertaxin) of CXCR1 and CXCR2. Structural and biochemical data are consistent with a noncompetitive allosteric mode of interaction between CXCR1 and Repertaxin, which, by locking CXCR1 in an inactive conformation, prevents signaling. Repertaxin is an effective inhibitor of polymorphonuclear cell recruitment<jats:italic>in vivo</jats:italic>and protects organs against reperfusion injury. Targeting the Repertaxin interaction site of CXCR1 represents a general strategy to modulate the activity of chemoattractant receptors.</jats:p>
  • Description: <jats:p>The chemokine CXC ligand 8 (CXCL8)/IL-8 and related agonists recruit and activate polymorphonuclear cells by binding the CXC chemokine receptor 1 (CXCR1) and CXCR2. Here we characterize the unique mode of action of a small-molecule inhibitor (Repertaxin) of CXCR1 and CXCR2. Structural and biochemical data are consistent with a noncompetitive allosteric mode of interaction between CXCR1 and Repertaxin, which, by locking CXCR1 in an inactive conformation, prevents signaling. Repertaxin is an effective inhibitor of polymorphonuclear cell recruitment<jats:italic>in vivo</jats:italic>and protects organs against reperfusion injury. Targeting the Repertaxin interaction site of CXCR1 represents a general strategy to modulate the activity of chemoattractant receptors.</jats:p>
  • Footnote:
  • Access State: Open Access