Structure of the Chemokine Receptor CXCR3

趋化因子受体 CXCR3 的结构

基本信息

批准号：
8874106
负责人：
ELIAS LOLIS
金额：
$ 20.81万
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/8874106
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 differential expression experience graft vs host disease immune function in vivo interest medical schools protein-tyrosine sulfotransferase 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多种功能。 FDA 批准的大约 30% 的药物针对这些类型的受体。趋化因子受体属于 GPCR 的一个亚家族，由 8 kDa 的小蛋白激活，参与体内平衡和免疫反应。 CXCR3 是 20 种趋化因子受体之一，由 CXCL9、10 和 11 三种趋化因子激活，并参与将 CD4+ 1 型辅助细胞 (Th1) 或 CD8+ 细胞毒性 T 细胞募集到炎症组织以启动适当的免疫反应。这三种趋化因子受到不同的调节，因此在体内没有多余的作用，尽管它们在细胞研究中竞争与 CXCR3 的结合。这些趋化因子和 CXCR3 还与各种自身免疫性疾病、移植排斥和移植物抗宿主病、特异性感染和癌症有关。因此，这些趋化因子和CXCR3是许多疾病的有吸引力的治疗靶点。一种化合物 (AMG487) 未能通过治疗牛皮癣的 II 期临床试验，可能是由于其体内代谢所致。本申请的主要目标是利用 CXCR3 与小分子拮抗剂复合的结构生物学，为设计具有最佳治疗特性的其他拮抗剂提供基础。我们还对一个更基本的问题感兴趣：趋化因子如何结合其受体？找到这个问题的答案超出了本提案的范围，但根据以往纯化稳定趋化因子受体复合物的经验，我们打算探索在巴斯德毕赤酵母中创建一个表达 CXCR3、其每种趋化因子激动剂和两种趋化因子激动剂的克隆。其他蛋白质导致 CXCR3 与其每种趋化因子激动剂之间的亲和力和稳定性增加。