CRYSTAL STRUCTURE OF DCR3-TL1A COMPLEX

DCR3-TL1A复合物的晶体结构

• 批准号: 8169276
• 负责人: STEVEN G ALMO
• 金额: $ 0.18万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169276
• 关键词: Adopted; Architecture; Autoimmune Diseases; Binding; Biochemical; Complex; Computer Retrieval of Information on Scientific Projects Database; Cysteine-Rich Domain; Disease; Dissection; Family member; Funding; Generic Drugs; Grant; Immune response; Immunosuppressive Agents; Institution; Ligand Binding; Ligands; Link; Malignant Neoplasms; Mutagenesis; Proteins; Reporting; Research; Research Personnel; Resources; Rheumatoid Arthritis; Source; Structure; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; United States National Institutes of Health; base; decoy receptor 3; human disease; insight; novel; novel therapeutics; overexpression; receptor; stoichiometry

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Decoy Receptor 3 (DcR3) is a secreted immunosuppressive protein that belongs to the Tumor Necrosis Factor (TNF) receptor superfamily. Its overexpression has been closely linked to cancer and autoimmune diseases. The dissection of DcR3's functional mechanism is complicated by its ability to neutralize three different TNF ligands: FasL, LIGHT, and TL1A. Each of these ligands binds distinct functional receptors, resulting in unique immune responses. Defining the interactions between DcR3 and its ligands may provide new therapeutic opportunities to a variety of human diseases, including rheumatoid arthritis, Chron's disease and malignancies. Here, we report the crystal structures of unliganded DcR3 and the DcR3-TL1A complex. These structures show that TL1A adopts a tight homotrimeric organization and that DcR3 is an elongated soluble receptor with novel cysteine-rich-domain module architecture. Each DcR3 molecule binds the groove between two adjacent TL1A subunits, resulting in a 3:3 stoichiometry. This structural information, in combination with complementary mutagenesis and biochemical characterization, reveals a mode of receptor recognition distinct from other TNF family members. This study explains the structural basis of DcR3 as a generic decoy receptor that neutralizes multiple ligands and provides insight into the functional annotation of the immunological network involving DcR3.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 诱饵受体3（DCR3）是一种分泌的免疫抑制蛋白，属于肿瘤坏死因子（TNF）受体超家族。它的过表达与癌症和自身免疫性疾病密切相关。 DCR3功能机制的解剖因中和三种不同的TNF配体的能力而变得复杂，即FASL，Light和TL1A。这些配体中的每一个结合不同的功能受体，从而产生独特的免疫反应。定义DCR3及其配体之间的相互作用可能会为包括类风湿关节炎，Chron病和恶性肿瘤在内的各种人类疾病提供新的治疗机会。在这里，我们报告了非配体DCR3和DCR3-TL1A复合物的晶体结构。这些结构表明，TL1A采用了一个紧密的同型组织，而DCR3是具有新型半胱氨酸域模块架构的细长可溶性受体。每个DCR3分子都结合两个相邻TL1A亚基之间的凹槽，从而导致3：3化学计量。这种结构信息结合了互补诱变和生化特征，揭示了一种与其他TNF家族成员不同的受体识别方式。这项研究将DCR3的结构基础解释为中和多种配体的通用诱饵受体，并提供了涉及DCR3的免疫网络功能注释的见解。