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.
Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2 : prevention of reperfusion injury / R. Bertini, M. Allegretti, C. Bizzarri, A. Moriconi, M. Locati, G. Zampella, M.N. Cervellera, V. Di Cioccio, M.C. Cesta, E. Galliera, F.O. Martinez, R. Di Bitondo, G. Troiani, V. Sabbatini, G. D'Anniballe, R. Anacardio, J.C. Cutrin, B. Cavalieri, F. Mainiero, R. Strippoli, P. Villa, M. Di Girolamo, F. Martin, M. Gentile, A. Santoni, D. Corda, G. Poli, A. Mantovani, P. Ghezzi, F. Colotta. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 101:32(2004 Aug 10), pp. 11791-11796. [10.1073/pnas.0402090101]
Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2 : prevention of reperfusion injury
M. Locati;E. Galliera;A. Mantovani;
2004
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.
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