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

基本信息

批准号：
6511072
负责人：
ELIAS LOLIS
金额：
$ 24.74万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2004-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6511072
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

项目摘要

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）趋化因子代表哺乳动物免疫系统中最大的细胞因子家族。最近发现其中一些蛋白质及其受体与 HIV-1 感染的病理生理学有关。基质细胞衍生因子 SDF-1a 是一种趋化因子，是受体 CXCR4 的天然激动剂。 CXCR4 受体也被确定为 T 向性、合胞体诱导型 HIV-1 菌株的共同受体。 SDR-1a 通过与 CXCR4 结合，抑制这些病毒株感染细胞。从生理学角度来看，SDF-1a 是 B 细胞、中性粒细胞和单核细胞的有效化学引诱剂，并且在心脏发育中也发挥着作用。两种趋化因子 MIP-I 和 MIP-II 也由疱疹病毒 HHV-8 编码，该病毒与艾滋病患者的卡波西肉瘤有关。这些蛋白质在病毒生命周期中的确切作用尚不清楚，但有趣的是，MIP-I 和 MIP-II 具有血管生成作用，因此可能参与卡波西肉瘤中发生的血管形成。 MIP-II 是唯一与 CXC 和 CC 趋化因子受体具有高亲和力结合的趋化因子。它结合的三个受体是 HIV-1 辅助受体 CCR3、CCR5 和 CXCR4。尽管人类 SDF-1a 和 HHV-8 MIP-II 在 HIV-1 感染中很重要，但人们对它们与受体的相互作用知之甚少。 SDF-1a和MIP-II的三维结构将通过X射线晶体学测定。这些结构将构成使用趋化因子类似物的基于结构的方法的基础，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利用这些研究产生的信息来设计治疗 HIV-1 的小分子受体拮抗剂。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CCR2 and CCR5 receptor-binding properties of herpesvirus-8 vMIP-II based on sequence analysis and its solution structure.

基于序列分析及其溶液结构的疱疹病毒 8 vMIP-II 的 CCR2 和 CCR5 受体结合特性。

DOI：
10.1046/j.1432-1327.2001.02184.x
发表时间：
2001
期刊：
European journal of biochemistry
影响因子：
0
作者：
Shao,W;Fernandez,E;Sachpatzidis,A;Wilken,J;Thompson,DA;Schweitzer,BI;Lolis,E
通讯作者：
Lolis,E

Tertiary structure of thiopurine methyltransferase from Pseudomonas syringae, a bacterial orthologue of a polymorphic, drug-metabolizing enzyme.