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Chemokine receptor CXCR3: Allosteric binding site mapping by photoaffinity labeling and site-directed mutagenesis

趋化因子受体 CXCR3：通过光亲和标记和定点诱变进行变构结合位点定位

基本信息

批准号：
218725515
负责人：
Professor Dr. Dieter Braun, since 1/2016
金额：
--
依托单位：
Arbeitsgruppe Systems Biophysics
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/218725515?language=en
关键词：
Chemokine receptor CXCR3 Allosteric binding

项目摘要

The CXCR3 receptor is implicated in various pathological conditions, including autoimmune diseases (e.g., multiple sclerosis, psoriasis, and rheumatoid arthritis), transplant rejection, cancer, development and dissemination of metastases. The compounds having CXCR3 inhibitory activity would be very useful in treating or preventing these diseases. Despite the fact that CXCR3 counts as a very attractive pharmacological target, the receptor-ligand interactions responsible for the high affinity and noncompetitive (allosteric) antagonism are not yet structurally and functionally characterized. The main aspect of this research proposal is the structural and functional characterization of CXCR3 allosteric binding pocket used by AMG487. The photoaffinity labeling followed by mass spectrometry will be applied. Photoactivatable ligands are tools used in drug discovery and development, facilitating the identification of the binding site on the target protein. Additionally, site-directed mutagenesis and homology modeling will be used to complement the photoaffinity labeling experiments. With the aid of novel ligands, which are currently synthesized in my research group, the validation of obtained homology model and identified binding pocket will be preformed. The expected outcomes are the structural and functional description of allosteric binding pocket of CXCR3 and the accompanying pharmacophore model.

CXCR 3受体与多种病理学病症有关，包括自身免疫性疾病（例如，多发性硬化、牛皮癣和类风湿性关节炎）、移植排斥、癌症、转移的发展和扩散。具有CXCR 3抑制活性的化合物在治疗或预防这些疾病中将非常有用。尽管CXCR 3被认为是一个非常有吸引力的药理学靶点，但负责高亲和力和非竞争性（变构）拮抗作用的受体-配体相互作用尚未在结构和功能上表征。本研究计划的主要方面是AMG 487使用的CXCR 3变构结合口袋的结构和功能表征。将应用光亲和标记，然后进行质谱分析。光活化配体是药物发现和开发中使用的工具，有助于鉴定靶蛋白上的结合位点。此外，定点诱变和同源性建模将用于补充光亲和标记实验。本课题组目前正在合成新的配体，并将借助这些配体对所获得的同源模型和所鉴定的结合口袋进行验证。预期的结果是CXCR 3的变构结合口袋的结构和功能的描述和伴随的药效团模型。