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National Academy of Sciences, Proceedings of the National Academy of Sciences, 32(101), p. 11791-11796, 2004

DOI: 10.1073/pnas.0402090101

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Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: Prevention of reperfusion injury

Journal article published in 2004 by Riccardo Bertini, Marcello Allegretti, Cinzia Bizzarri, Alessio Moriconi, Massimo Locati, Giuseppe Zampella, Maria N. Cervellera, Cervellera Mn, Vito Di Cioccio, Maria C. Cesta, Cesta Mc, Emanuela Galliera, Martinez Fo, Fernando O. Martinez, Rosa Di Bitondo and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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 in vivo and protects organs against reperfusion injury. Targeting the Repertaxin interaction site of CXCR1 represents a general strategy to modulate the activity of chemoattractant receptors.