RESUMO
Chemokines are a family of small proteins that are present in a variety of inflammatory conditions and have been shown to activate and recruit a wide variety of cell types. They bind to a family of seven transmembrane G-protein-coupled receptors. Models for the interaction of the chemokines with their receptors suggest a two-step mechanism. Initially, the main body of the chemokine interacts with the outside of the receptor (Site 1), and this interaction directs receptor selectivity. Subsequently, the flexible amino-terminus of the chemokine interacts with the receptor core (Site 2) to initiate the signaling response. Mutagenesis studies of IL-8, the archetypal CXC chemokine, show that altering the protein on the third beta-sheet can change the receptor selectivity from that of a CXC chemokine and introduce CC chemokine activity-confirming the role of this region in Site 1. Mutagenesis studies of the amino-terminal region of IL-8 showed that a tripeptide, ELR, was essential for the interaction with Site 2. We have shown, using synthetic peptides and site-directed mutagenesis, that the amino-terminus of RANTES is important in the signaling response (Site 2). Mutations that alter only the interaction with Site 2 are capable of binding the receptor and not signaling and are therefore potential antagonists. Such antagonists have now been made by several groups, for a number of the chemokine receptors, and are active at nanomolar concentrations. These can now be used to test the hypothesis that antagonism of chemokine receptors will lead to a reduction in inflammation in vivo.
