Structure of the Chemokine Receptor CXCR3

趋化因子受体 CXCR3 的结构

基本信息

批准号：
8773139
负责人：
ELIAS LOLIS
金额：
$ 24.98万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8773139
关键词：
AMD3100 Affinity Agonist Autoimmune Diseases Autologous Bone Marrow Transplantation Binding Bone Marrow CCR5 gene CD34 gene CD8B1 gene CXCL10 gene CXCL11 gene CXCL12 gene CXCL9 gene CXCR3 gene CXCR4 Receptors CXCR4 gene Cells Chemotaxis Collaborations Complex Crystallization Crystallography Cytotoxic T-Lymphocytes Data Data Collection Disease Doxepin Drug Targeting Equipment Escherichia coli FDA approved Foundations Functional disorder G-Protein-Coupled Receptors Goals Graft Rejection Growth HIV HIV-1 Health Hematopoietic Hematopoietic stem cells Histamine H1 Receptors Homeostasis Human Immune response Immunologic Adjuvants Infection Inflammatory Interferons Learning Letters Ligands Location Malignant Neoplasms Membrane Proteins Metabolism Metastatic to Muramidase Natural Immunity Netherlands Pharmaceutical Chemistry Phase Phase II Clinical Trials Photons Postdoctoral Fellow Property Proteins Psoriasis Recruitment Activity Research Institute Role Scientist Source Structure System T-Lymphocyte Technology Therapeutic Tissues adaptive immunity base biophysical properties cell motility chemokine chemokine receptor design experience graft vs host disease immune function in vivo interest medical schools protein-tyrosine sulfotransferase public health relevance receptor receptor function reconstitution small molecule structural biology therapeutic target

项目摘要

DESCRIPTION (provided by applicant): G-protein coupled receptors (GPCRs) have many functions in human health and disease. About 30% of FDA approved drugs target these types of receptors. Chemokine receptors belong to a subfamily of GPCRs, are activated by small proteins of 8 kDa, and are involved in homeostasis and the immune response. CXCR3 is one of 20 chemokine receptors, is activated by three chemokines, CXCL9, 10, and 11, and is involved in recruiting CD4+ type-1 helper (Th1) or CD8+ cytotoxic T-cells to inflammatory tissues to initiate an appropriate immune response. These three chemokines are differentially regulated and, therefore, do not have redundant roles in vivo although they compete for binding to CXCR3 in cellular studies. These chemokines and CXCR3 are also involved in various autoimmune diseases, transplant rejection and graft versus host disease, specific infections, and cancer. Therefore, these chemokines and CXCR3 are attractive therapeutic targets for a number of diseases. One compound (AMG487) failed Phase II clinical trials for psoriasis, presumably due to its in vivo metabolism. The main goal in this application is to use structural biology of CXCR3 complexed to a small molecule antagonist to provide the foundation for the design of other antagonists with the optimum properties for a therapeutic. We are also interested in a more fundamental question: how do chemokines bind their receptors? Finding an answer to this question is beyond the scope of this proposal, but based on previous experience to purify a stable chemokine-receptor complex, we intend to explore creating a clone in P. pastoris expressing CXCR3, each of its chemokine agonists, and two other proteins that result in increased the affinity and stability between CXCR3 and each of its chemokine agonists.

描述（由申请人提供）：G蛋白偶联受体（GPCR）在人类健康和疾病中具有许多功能。大约30％的FDA批准药物靶向这类受体。趋化因子受体属于GPCR的亚科，被8 kDa的小蛋白激活，并参与体内平衡和免疫反应。 CXCR3是20个趋化因子受体之一，由三种趋化因子CXCL9、10和11激活，并且参与招募CD4+型1助手（TH1）或CD8+细胞毒性T细胞以炎症组织以启动适当的免疫反应。这三种趋化因子受到差异调节，因此在体内没有冗余作用，尽管它们在细胞研究中竞争与CXCR3结合。这些趋化因子和CXCR3也参与了各种自身免疫性疾病，移植排斥以及移植物与宿主疾病，特定感染和癌症。因此，这些趋化因子和CXCR3是多种疾病的有吸引力的治疗靶标。一种化合物（AMG487）失败了牛皮癣的II期临床试验，可能是由于其体内代谢。该应用程序的主要目的是使用与小分子拮抗剂复合的CXCR3的结构生物学，为具有最佳特性的其他拮抗剂设计为治疗性提供了基础。我们也对一个更基本的问题感兴趣：趋化因子如何束缚其受体？找到这个问题的答案超出了该提案的范围，但是基于以前的经验净化稳定的趋化因子受体络合物复合体，我们打算探索在P. p. p. p. p. p. p. p. cxcr3中创建克隆，每种趋化因子激动剂，另外两种蛋白质，从而提高了CXCR3和每种氧化物磷脂的亲和力和稳定性。