Allosteric trans-inhibition by specific antagonists in CCR2/CXCR4 heterodimers

doi:10.1074/jbc.M705302200

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Papers In Press, published online ahead of print August 22, 2007
J. Biol. Chem, 10.1074/jbc.M705302200
Submitted on June 28, 2007
Revised on August 13, 2007
Accepted on August 22, 2007

Allosteric trans-inhibition by specific antagonists in CCR2/CXCR4 heterodimers

Denis Sohy, Marc Parmentier, and Jean-Yves Springael

IRIBHM, Université Libre de Bruxelles, Brussels, Brussels 1070

Corresponding Author: mparment{at}ulb.ac.be

Chemokine receptors are presently used as targets for candidate drugs in the frame of inflammatory diseases and HIV 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.

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