Conformational duality in the human chemokine Ltn/XCL1

人类趋化因子 Ltn/XCL1 的构象二元性

基本信息

  • 批准号:
    7407385
  • 负责人:
  • 金额:
    $ 26.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-04-01 至 2010-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The goal of this work is to understand the structural and biochemical basis for the recruitment of lymphocytes by human Lymphotactin, a chemokine that defies the traditional paradigm by interconverting between two entirely different tertiary structures. Inflammation in the vertebrate immune system is orchestrated by approximately 50 chemokines that specifically activate members of a group of 20 G protein-coupled receptors. These secreted signaling proteins also bind extracellular matrix glycosaminoglycans (GAG) in order to direct migration along a gradient of chemokine concentration. Lymphotactin (Ltn/XCL1), the prototype and single member of the C class of chemokines, acts through its cognate receptor XCR1 to selectively recruit T and NK cells. Functional roles in tumor regression and tissue transplant rejection highlight two disease states that may respond to treatment with either Ltn mimetics or antagonists. Ltn contains only one of the two disulfides conserved in all other chemokines, and is further distinguished by a unique disordered C-terminal extension that is essential for activity. A consequence of these divergent sequence features is that Ltn simultaneously adopts two distinct tertiary structures in physiological solution conditions, only one of which resembles the canonical chemokine fold. Experiments in Specific Aim 1 will use NMR spectroscopy and mutagenesis to determine the novel non-chemokine structure of Ltn, measure the dynamics of interconversion, and test the hypothesis that its conformational equilibrium derives from the lack of a conserved disulfide bridge. The goal of Aim 2 is to alter the conformational equilibrium and measure binding affinities for each species by surface plasmon resonance, in order to test the hypothesis that the structural interconversion creates a high affinity GAG binding site essential for in vivo activity. In Specific Aim 3, conserved residues in the essential C-terminus will be probed for their role in GPCR activation, and comparisons of activity in vitro and in vivo for conformationally-restricted Ltn variants will be compared in order to test the hypothesis that only the chemokine-like structure is competent to bind and activate the receptor. These structural and biochemical studies are designed to open new avenues for in vivo modulation of lymphocyte trafficking directed by Lymphotactin.
描述(由申请人提供):这项工作的目标是了解人趋化因子(一种通过在两种完全不同的三级结构之间相互转换而违背传统范式的趋化因子)募集淋巴细胞的结构和生化基础。脊椎动物免疫系统中的炎症由大约50种趋化因子协调,这些趋化因子特异性地激活一组20种G蛋白偶联受体的成员。这些分泌的信号蛋白也结合细胞外基质糖胺聚糖(GAG),以引导沿着趋化因子浓度梯度的迁移。趋化因子C类的原型和单一成员趋化因子趋化因子趋化蛋白(Ltn/XCL 1)通过其同源受体XCR 1选择性地募集T细胞和NK细胞。在肿瘤消退和组织移植排斥中的功能作用突出了两种可能对Ltn模拟物或拮抗剂治疗有反应的疾病状态。Ltn仅包含在所有其他趋化因子中保守的两个二硫化物中的一个,并且通过对活性至关重要的独特的无序C-末端延伸进一步区分。这些不同的序列特征的结果是,Ltn在生理溶液条件下同时采用两种不同的三级结构,其中只有一种类似于典型的趋化因子折叠。具体目标1中的实验将使用NMR光谱和诱变来确定Ltn的新型非趋化因子结构,测量相互转化的动力学,并测试其构象平衡源于缺乏保守二硫键的假设。目的2的目标是通过表面等离子体共振改变构象平衡并测量每种物质的结合亲和力,以检验结构互变产生体内活性所必需的高亲和力GAG结合位点的假设。在特定目标3中,将探测必需C末端中的保守残基在GPCR活化中的作用,并将比较构象限制性Ltn变体的体外和体内活性,以检验仅趋化因子样结构能够结合和活化受体的假设。这些结构和生物化学研究旨在开辟新的途径,在体内调节淋巴细胞的运输直接由aplphotactin。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Brian F Volkman其他文献

Brian F Volkman的其他文献

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{{ truncateString('Brian F Volkman', 18)}}的其他基金

Evolution and design of metamorphic fold-switching proteins
变态折叠转换蛋白的进化和设计
  • 批准号:
    10733814
  • 财政年份:
    2023
  • 资助金额:
    $ 26.41万
  • 项目类别:
Evolution of fold-switching in the metamorphic chemokine XCL1
变质趋化因子 XCL1 中折叠转换的进化
  • 批准号:
    10475442
  • 财政年份:
    2021
  • 资助金额:
    $ 26.41万
  • 项目类别:
Targeting CCL28 as therapy for obstructive lung disease
靶向 CCL28 治疗阻塞性肺病
  • 批准号:
    9282770
  • 财政年份:
    2015
  • 资助金额:
    $ 26.41万
  • 项目类别:
Structural and energetic origins of metamorphic protein folding
变质蛋白质折叠的结构和能量起源
  • 批准号:
    8735210
  • 财政年份:
    2013
  • 资助金额:
    $ 26.41万
  • 项目类别:
Sulfotyrosine-guided discovery of small molecule chemokine inhibitors
磺基酪氨酸引导的小分子趋化因子抑制剂的发现
  • 批准号:
    8084410
  • 财政年份:
    2011
  • 资助金额:
    $ 26.41万
  • 项目类别:
Sulfotyrosine-guided discovery of small molecule chemokine inhibitors
磺基酪氨酸引导的小分子趋化因子抑制剂的发现
  • 批准号:
    8324405
  • 财政年份:
    2011
  • 资助金额:
    $ 26.41万
  • 项目类别:
Sulfotyrosine-guided discovery of small molecule chemokine inhibitors
磺基酪氨酸引导的小分子趋化因子抑制剂的发现
  • 批准号:
    8447040
  • 财政年份:
    2011
  • 资助金额:
    $ 26.41万
  • 项目类别:
Sulfotyrosine-guided discovery of small molecule chemokine inhibitors
磺基酪氨酸引导的小分子趋化因子抑制剂的发现
  • 批准号:
    8639582
  • 财政年份:
    2011
  • 资助金额:
    $ 26.41万
  • 项目类别:
Conformational duality in the human chemokine Ltn/XCL1
人类趋化因子 Ltn/XCL1 的构象二元性
  • 批准号:
    8301087
  • 财政年份:
    2011
  • 资助金额:
    $ 26.41万
  • 项目类别:
Sulfotyrosine-guided discovery of small molecule chemokine inhibitors
磺基酪氨酸引导的小分子趋化因子抑制剂的发现
  • 批准号:
    8245006
  • 财政年份:
    2011
  • 资助金额:
    $ 26.41万
  • 项目类别:

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