ANALYSIS OF CO EVOLUTION OF LIGAND RECEPTOR BINDING SPECIFICITIES: HIV

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Chemokines are small secretory or membrane bound proteins, approximately 120 amino acid residues, involved in chemotaxis of leukocyte subpopulations and specific induction of endothelial cell adhesion. They constitute a large family of chemotactic cytokines that act at G protein-coupled receptors to regulate diverse biological processes, including leukocyte trafficking, angiogenesis, and hematopoiesis. Recently, it was found that chemokines RANTES, MIP1a, MIP1b, and SDF-1 were potent inhibitors of HIV infection. The chemokine receptors of these chemokines, CCR5 and CXCR4 were shown to be the main co-receptors to CD4 in HIV infection. CCR5 and CD4 are coreceptors in monocyte/macrophage-tropic HIV strains and CXCR4 and CD4 are coreceptors in the lymphocyte-tropic HIV strains. Not only do chemokines play a role in HIV, but they also exert other biological effects in inflammatory conditions and in malignant tumors. Chemokines like PF4, IP10, and MIG are angiostatic and induce tumor regression by reducing the tumor blood supply. However, IL8, which is angiogenic, can promote tumor growth. These and other results suggest the potential therapeutic utility that chemokines have in the area of inflammation, cancer, and infectious disease. We are using structure and sequence analysis techniques in order to predict the ligand binding specificity of the chemokine receptors. In particular, we are focusing on three different issues: 1) analyze ligand-receptor binding contacts; 2) study structural motifs involved with binding; 3) study correlations in the way that ligands and their receptors co-evolve.