Structure of the Chemokine Receptor CXCR3

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批准的药物靶向这些类型的受体。 趋化因子受体属于GPCR的亚家族，由8 kDa的小蛋白激活，并且参与稳态和免疫应答。 CXCR 3是20种趋化因子受体之一，由三种趋化因子CXCL 9、10和11激活，并参与将CD 4 + 1型辅助细胞（Th 1）或CD 8+细胞毒性T细胞募集到炎性组织以启动适当的免疫应答。这三种趋化因子是差异调节的，因此，虽然它们在细胞研究中竞争与CXCR 3的结合，但在体内没有多余的作用。这些趋化因子和CXCR 3也参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。 因此，这些趋化因子和CXCR 3是许多疾病的有吸引力的治疗靶点。一种化合物（AMG 487）在银屑病II期临床试验中失败，可能是由于其体内代谢。 本申请的主要目的是利用与小分子拮抗剂复合的CXCR 3的结构生物学，为设计具有最佳治疗性质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：趋化因子如何结合它们的受体？找到这个问题的答案超出了这个提议的范围，但是基于先前纯化稳定的趋化因子-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表达CXCR 3、其每种趋化因子激动剂以及导致CXCR 3与其每种趋化因子激动剂之间的亲和力和稳定性增加的另外两种蛋白质的克隆。

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.