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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.

Original publication

DOI

10.1073/pnas.0402090101

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

08/2004

Volume

101

Pages

11791 - 11796

Addresses

Dompé, 67100 L'Aquila, Italy.

Keywords

Animals, Humans, Rats, Liver Diseases, Reperfusion Injury, Inflammation, Sulfonamides, Receptors, Interleukin-8A, Signal Transduction, Allosteric Regulation, Binding Sites, Protein Conformation, Structure-Activity Relationship, Models, Molecular