ANALYSIS OF CO EVOLUTION OF LIGAND RECEPTOR BINDING SPECIFICITIES: HIV

趋化因子是一种小的分泌或膜结合蛋白， 大约120个氨基酸残基，参与趋化作用 白细胞亚群与内皮细胞的特异性诱导 粘附力。它们构成了趋化细胞因子的大家族 它们作用于G蛋白偶联受体来调节不同的生物 过程，包括白细胞贩运，血管生成，以及 造血术。最近发现趋化因子RANTES、MIP1a、 MIP1b和SDF-1是HIV感染的有效抑制因子。这个 趋化因子受体CCR5和CXCR4被证明是 是HIV感染中的主要辅助受体。CCR5和CD4是 嗜单核/巨噬细胞的HIV毒株和CXCR4和CXCR4的辅助受体 在嗜淋巴细胞的HIV毒株中，CD4是辅助受体。不仅是因为 趋化因子在艾滋病毒中发挥作用，但它们也发挥其他生物学作用 对炎症条件和恶性肿瘤的影响。 趋化因子如PF4、IP10和MIG具有血管抑制作用，可诱发肿瘤 通过减少肿瘤血供而消退。然而，IL8，也就是 血管生成，可促进肿瘤生长。这些和其他结果表明 趋化因子在肺癌领域的潜在治疗作用 炎症、癌症和传染病。我们使用的是结构 和序列分析技术，以预测配体 趋化因子受体的结合特异性。特别是，我们正在 重点研究三个不同的问题：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) 研究配体及其受体的相互关系 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.