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J. Biol. Chem., Vol. 282, Issue 41, 30062-30069, October 12, 2007

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Allosteric Transinhibition by Specific Antagonists in CCR2/CXCR4 Heterodimers^*

From the Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles, Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium

Chemokine receptors are presently used as targets for candidate drugs in the frame of inflammatory diseases and human immunodeficiency virus infection. They were shown to dimerize, but the functional relevance of dimerization in terms of drug action remains poorly understood. We reported previously the existence of negative binding cooperativity between the subunits of CCR2/CCR5 heterodimers. In the present study, we extend these observations to heterodimers formed by CCR2 and CXCR4, which are more distantly related. We also show that specific antagonists of one receptor inhibit the binding of chemokines to the other receptor as a consequence of their heterodimerization, both in recombinant cell lines and primary leukocytes. This resulted in a significant functional cross-inhibition in terms of calcium mobilization and chemotaxis. These data demonstrate that chemokine receptor antagonists regulate allosterically the functional properties of receptors on which they do not bind directly, with important implications on the effects of these potential therapeutic agents.

Received for publication, June 28, 2007 , and in revised form, August 13, 2007.

^* This work was supported by the Actions de Recherche Concertéesofthe Communauté Française de Belgique, Interuniversity Attraction Poles Programme P6-14 (Belgian State, Belgian Science Policy), European Union Grants LSHB-CT-2003-503337/GPCRs and LSHB-CT-2005-518167/INNOCHEM, the French Agence Nationale de Recherche sur le SIDA, the Fonds de la Recherche Scientifique Médicale of Belgium, and the Fondation Médicale Reine Elisabeth. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and supplemental Table S1.

¹ Fellow of the Belgian Fonds pour la formation à la Recherche dans l'Industrie et l'Agriculture.

² To whom correspondence should be addressed. E-mail: mparment{at}ulb.ac.be.

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