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J. Biol. Chem., Vol. 282, Issue 38, 27935-27943, September 21, 2007

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Small Molecule Receptor Agonists and Antagonists of CCR3 Provide Insight into Mechanisms of Chemokine Receptor Activation^*

Emma L. Wise, Cécile Duchesnes, Paula C. A. da Fonseca, Rodger A. Allen^¶, Timothy J. Williams, and James E. Pease¹

From the Leukocyte Biology Section, National Heart and Lung Institute Division, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London SW7 2AZ, Structural Electron Microscopy Team, Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, and ^¶UCB-Celltech, Slough SL1 3WE, United Kingdom

Chemokine receptor CCR3 is highly expressed by eosinophils and signals in response to binding of the eotaxin family of chemokines, which are up-regulated in allergic disorders. Consequently, CCR3 blockade is of interest as a possible therapeutic approach for the treatment of allergic disease. We have described previously a bispecific antagonist of CCR1 and CCR3 named UCB35625 that was proposed to interact with the transmembrane residues Tyr-41, Tyr-113, and Glu-287 of CCR1, all of which are conserved in CCR3. Here, we show that cells expressing the CCR3 constructs Y113A and E287Q are insensitive to antagonism by UCB35625 and also exhibit impaired chemotaxis in response to CCL11/eotaxin, suggesting that these residues are important for antagonist binding and also receptor activation. Furthermore, mutation of the residue Tyr-113 to alanine was found to turn the antagonist UCB35625 into a CCR3 agonist. Screens of small molecule libraries identified a novel specific agonist of CCR3 named CH0076989. This was able to activate eosinophils and transfectants expressing both wild-type CCR3 and a CCR1–CCR3 chimeric receptor lacking the CCR3 amino terminus, indicating that this region of CCR3 is not required for CH0076989 binding. A direct interaction with the transmembrane helices of CCR3 was supported by mutation of the residues Tyr-41, Tyr-113, and Glu-287 that resulted in complete loss of CH0076989 activity, suggesting that the compound mimics activation by CCL11. We conclude that both agonists and antagonists of CCR3 appear to occupy overlapping sites within the transmembrane helical bundle, suggesting a fine line between agonism and antagonism of chemokine receptors.

Received for publication, April 18, 2007 , and in revised form, June 6, 2007.

^* This work was supported by the Wellcome Trust, Project Grant 076036/Z/04/Z. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 44-20-7594-3162; Fax: 44-20-7594-3119; E-mail: j.pease{at}imperial.ac.uk.

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