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.

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 诱骗受体3（DcR 3）是一种分泌型免疫抑制蛋白，属于肿瘤坏死因子（TNF）受体超家族。它的过度表达与癌症和自身免疫性疾病密切相关。DcR 3的功能机制的剖析是复杂的，因为它能够中和三种不同的TNF配体：FasL，LIGHT和TL 1A。这些配体中的每一种都结合不同的功能受体，导致独特的免疫应答。明确DcR 3与配体之间的相互作用可能为治疗类风湿性关节炎、克隆病和恶性肿瘤等多种人类疾病提供新的机会。在这里，我们报告了未配体的DcR 3和DcR 3-TL 1A复合物的晶体结构。这些结构表明TL 1A采用紧密的同源三聚体组织，并且DcR 3是具有新颖的富含半胱氨酸的结构域模块架构的延长的可溶性受体。每个DcR 3分子与两个相邻的TL 1A亚基之间的凹槽结合，产生3：3的化学计量比。这种结构信息，结合互补诱变和生化表征，揭示了不同于其他TNF家族成员的受体识别模式。这项研究解释了DcR 3作为一种通用诱饵受体的结构基础，该受体可中和多种配体，并为涉及DcR 3的免疫网络的功能注释提供了见解。