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Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury.
Bertini R,
Allegretti M,
Bizzarri C,
Moriconi A,
Locati M,
Zampella G,
Cervellera MN,
Di Cioccio V,
Cesta MC,
Galliera E,
Martinez FO,
Di Bitondo R,
Troiani G,
Sabbatini V,
D'Anniballe G,
Anacardio R,
Cutrin JC,
Cavalieri B,
Mainiero F,
Strippoli R,
Villa P,
Di Girolamo M,
Martin F,
Gentile M,
Santoni A,
Corda D,
Poli G,
Mantovani A,
Ghezzi P,
Colotta F.
Dompé, 67100 L'Aquila, Italy.
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.
PMID: 15282370 [PubMed - indexed for MEDLINE]
PMCID: PMC511013
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Cited by 4 PubMed Central articles
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Mediators of neutrophil recruitment in human abdominal aortic aneurysms.
Houard X, Touat Z, Ollivier V, Louedec L, Philippe M, Sebbag U, Meilhac O, Rossignol P, Michel JB.
Cardiovasc Res. 2009 Jun 1; 82(3):532-41. Epub 2009 Feb 5.
[Cardiovasc Res. 2009]
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Deregulation of a STAT3-interleukin 8 signaling pathway promotes human glioblastoma cell proliferation and invasiveness.
de la Iglesia N, Konopka G, Lim KL, Nutt CL, Bromberg JF, Frank DA, Mischel PS, Louis DN, Bonni A.
J Neurosci. 2008 Jun 4; 28(23):5870-8.
[J Neurosci. 2008]
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CXCR2 chemokine receptor antagonism enhances DOP opioid receptor function via allosteric regulation of the CXCR2-DOP receptor heterodimer.
Parenty G, Appelbe S, Milligan G.
Biochem J. 2008 Jun 1; 412(2):245-56.
[Biochem J. 2008]
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