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

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.

SUBMITTER: Bertini R 

PROVIDER: S-EPMC511013 | biostudies-literature | 2004 Aug

REPOSITORIES: biostudies-literature

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

Bertini Riccardo R   Allegretti Marcello M   Bizzarri Cinzia C   Moriconi Alessio A   Locati Massimo M   Zampella Giuseppe G   Cervellera Maria N MN   Di Cioccio Vito V   Cesta Maria C MC   Galliera Emanuela E   Martinez Fernando O FO   Di Bitondo Rosa R   Troiani Giulia G   Sabbatini Vilma V   D'Anniballe Gaetano G   Anacardio Roberto R   Cutrin Juan C JC   Cavalieri Barbara B   Mainiero Fabrizio F   Strippoli Raffaele R   Villa Pia P   Di Girolamo Maria M   Martin Franck F   Gentile Marco M   Santoni Angela A   Corda Daniela D   Poli Giuseppe G   Mantovani Alberto A   Ghezzi Pietro P   Colotta Francesco F  

Proceedings of the National Academy of Sciences of the United States of America 20040728 32

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 effec  ...[more]

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