Abstract
Chemokine receptor antagonists appear to access two distinct binding sites on different members of this receptor family. One class of CCR4 antagonists has been suggested to bind to a site accessible from the cytoplasm while a second class did not bind to this site. In this report, we demonstrate that antagonists representing a variety of structural classes bind to two distinct allosteric sites on CCR4. The effects of pairs of low-molecular weight and/or chemokine CCR4 antagonists were evaluated on CCL17- and CCL22-induced responses of human CCR4+ T cells. This provided an initial grouping of the antagonists into sets which appeared to bind to distinct binding sites. Binding studies were then performed with radioligands from each set to confirm these groupings. Some novel receptor theory was developed to allow the interpretation of the effects of the antagonist combinations. The theory indicates that, generally, the concentration-ratio of a pair of competing allosteric modulators is maximally the sum of their individual effects while that of two modulators acting at different sites is likely to be greater than their sum. The low-molecular weight antagonists could be grouped into two sets on the basis of the functional and binding experiments. The antagonistic chemokines formed a third set whose behaviour was consistent with that of simple competitive antagonists. These studies indicate that there are two allosteric regulatory sites on CCR4.
Highlights
The chemokines are a family of small proteins which act as leucocyte chemoattractants.They may be subdivided into four families based on the arrangement of the first two of four conserved cysteine residues
We demonstrate that the interactions of a range of CCR4 antagonists, are consistent with the presence of two distinct binding sites for low-molecular
CCR4 antagonists to investigate the number of binding sites on the receptor
Summary
8–10 kDa) proteins which act as leucocyte chemoattractants They may be subdivided into four families based on the arrangement of the first two of four conserved cysteine residues. The largest of these families are the CC-chemokines in which the cysteine residues are adjacent and the British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. The chemokine receptors are Gi-protein coupled receptors and are divided into four families, based on their ligand specificity, for example CC-chemokines are agonists for CC-chemokine receptors while CXCchemokine receptors respond only to CXC-chemokines (Murphy et al 2000).
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