SDF-1A AND MIP-II INTERACTIONS WITH CHEMOKINE RECEPTORS

SDF-1A 和 MIP-II 与趋化因子受体的相互作用

• 批准号: 6170795
• 负责人: ELIAS LOLIS
• 金额: $ 23.32万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170795
• 关键词: HIV infections; Saccharomyces cerevisiae; X ray crystallography; analog; antiAIDS agent; cytokine receptors; drug design /synthesis /production; human immunodeficiency virus 1; macrophage inflammatory proteins; mutant; protein protein interaction; protein structure function; receptor binding; receptor coupling; receptor expression; stimulant /agonist

DESCRIPTION: (Adapted from Applicant's Abstract) Chemokines represent the largest family of cytokines in the mammalian immune system. Some of these proteins and their receptors have recently been found to be involved in the pathophysiology of HIV-1 infection. One chemokine, stromal cell-derived factor SDF-1a is the natural agonist for the receptor CXCR4. The CXCR4 receptor has also been identified as the co-receptor for T-tropic, syncytium inducing strains of HIV-1. By virtue of its binding to CXCR4, SDR-1a inhibits these viral strains from infecting cells. Physiologically, SDF-1a is a potent chemoattractant for B-cells, neutrophils, and monocytes and also plays a role in cardiac development. Two chemokines, MIP-I and MIP-II, are also encoded by the herpesvirus HHV-8, a virus associated with Kaposi's sarcoma in AIDS patients. The exact role of these proteins in the viral life cycle is not known, but it is interesting that MIP-I and MIP-II are angiogenic, and therefore may be involved in the vascularization that occurs in Kaposi's sarcoma. MIP-II is the only chemokine to possess high affinity binding with CXC and CC chemokine receptors. Three of the receptors to which it binds are HIV-1 co-receptors CCR3, CCR5, and CXCR4. Despite the importance of human SDF-1a and HHV-8 MIP-II in HIV-1 infection, very little is known about their interactions with receptors. The three dimensional structures of SDF-1a and MIP-II will be determined by X-ray crystallography. These structures will form the basis of a structure-based approach using analogues of the chemokines to gain an understanding of the molecular details of chemokine-receptor interactions. The ultimate aim of this work is to use the information generated from these studies in the design of small molecule receptor antagonists for the treatment of HIV-1.

描述：（改编自申请人的摘要）趋化因子代表了哺乳动物免疫系统中最大的细胞因子家族。这些蛋白质中的一些及其受体最近被发现与HIV-1感染的病理生理有关。一种趋化因子，基质细胞衍生的因子SDF-1A是受体CXCR4的天然激动剂。 CXCR4受体也已被鉴定为诱导HIV-1的T-热带诱导菌株的共受体。 SDR-1A凭借其与CXCR4的结合，抑制了感染细胞的这些病毒菌株。从生理上讲，SDF-1A是B细胞，中性粒细胞和单核细胞的有效趋化剂，并且在心脏发育中也起作用。两种趋化因子MIP-I和MIP-II也由疱疹病毒HHV-8编码，这是一种与Kaposi的艾滋病患者相关的病毒。这些蛋白质在病毒生命周期中的确切作用尚不清楚，但是有趣的是，MIP-I和MIP-II具有血管生成，因此可能与Kaposi肉瘤中发生的血管化有关。 MIP-II是唯一具有与CXC和CC趋化因子受体高亲和力结合的趋化因子。与其结合的三个受体是HIV-1共受体CCR3，CCR5和CXCR4。尽管人类SDF-1A和HHV-8 MIP-II在HIV-1感染中的重要性很重要，但对它们与受体的相互作用知之甚少。 SDF-1A和MIP-II的三维结构将由X射线晶体学确定。这些结构将使用趋化因子的类似物构成基于结构方法的基础，以了解趋化因子受体相互作用的分子细节。这项工作的最终目的是将这些研究从小分子受体拮抗剂设计中产生的信息用于治疗HIV-1。