ANALYSIS OF CO EVOLUTION OF LIGAND RECEPTOR BINDING SPECIFICITIES: HIV

趋化因子是小的分泌或膜结合蛋白， 大约120个氨基酸残基，参与趋化性 白细胞亚群与内皮细胞特异性诱导 粘连 它们构成了一个大家族的趋化细胞因子 作用于G蛋白偶联受体， 过程，包括白细胞运输，血管生成， 造血 最近，发现趋化因子RANTES，MIP 1a， MIP 1b和SDF-1是HIV感染的有效抑制剂。 的 这些趋化因子的趋化因子受体CCR 5和CXCR 4显示出 是HIV感染中CD 4的主要共受体。 CCR 5和CD 4是 单核细胞/巨噬细胞嗜性HIV毒株和CXCR 4中的辅助受体 CD 4是嗜淋巴细胞的HIV毒株中的辅助受体。 不仅 趋化因子在HIV中发挥作用，但它们也发挥其他生物学作用。 在炎症和恶性肿瘤中的作用。 趋化因子如PF 4、IP 10和VEGF具有血管抑制作用并诱导肿瘤 通过减少肿瘤的血液供应来消退。 然而，IL 8， 血管生成，可以促进肿瘤生长。 这些和其他结果表明， 趋化因子在以下领域具有的潜在治疗效用： 炎症、癌症和传染病。 我们使用结构 和序列分析技术来预测配体 趋化因子受体的结合特异性。 我们尤其 重点研究了三个不同的问题：1）分析配体-受体 结合接触; 2）研究与结合有关的结构基序; 3） 研究配体和它们的受体 共同进化

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.