STRUCTURAL STUDIES OF PHOSPHOINOSITIDE RELATED PROTEIN KINASES

磷酸肌醇相关蛋白激酶的结构研究

• 批准号: 7609789
• 负责人: Gerwald Jogl
• 金额: $ 23.77万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609789
• 关键词: 1-Phosphatidylinositol 4-Kinase; Binding; Binding Sites; C-terminal; Catalysis; Catalytic Domain; Cell physiology; Cells; Class; Clinical; Computer Retrieval of Information on Scientific Projects Database; DNA Damage; Enzymes; Family; Family member; Funding; Grant; Human; Institution; KRP protein; Laboratories; Malignant Neoplasms; Molecular Weight; Oxidative Stress; Phosphatidylinositols; Phosphotransferases; Pik-off; Positioning Attribute; Protein Kinase; Proteins; Research; Research Personnel; Resources; Roentgen Rays; Sequence Homology; Signal Pathway; Source; Structure; Substrate Specificity; Testing; United States National Institutes of Health; base; cancer therapy; human CHEK1 protein; human FAT protein; human FRAP1 protein; inhibitor/antagonist; protein structure; research study; small molecule; wortmannin

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. The phosphoinositide kinase related protein kinases (PIKK) mTOR, ATM and ATR have crucial cellular functions. mTOR is a central effector kinase in the PI3K/Akt signaling pathway that is frequently dysregulated in human cancers. ATM and ATR are essential cell cycle checkpoint kinases in the DNA damage signaling pathway, protecting cells against DNA damage and oxidative stress. Inhibitors against mTOR are currently in clinical cancer therapy trials. Additional selective inhibitors against these enzymes could have numerous applications in laboratory experiments and might be of clinical value for the treatment of cancer. mTOR, ATM and ATR are large proteins with molecular weights of 288, 350, and 300kDa, respectively. They contain a conserved C-terminal region, consisting of a FAT domain, a catalytic PIKK protein kinase domain and a FATC domain. The catalytic domain of all three proteins shares sequence homology with phosphoinositide kinases (PIK), such as phosphatidylinositol 3- and 4kinases (PI3K, PI4K). All PIK and PIKK catalytic domains are inhibited by the small-molecule inhibitor wortmannin, which binds to the ATP binding site. Despite the functional importance of PIKKs, only one protein structure of class I PI3K is currently available as a template for this enzyme family. Here, we propose to determine X-ray crystal structures of the catalytic domains of PIKs and PIKKs to investigate the structural basis of enzymatic catalysis and substrate specificity. We will test the hypothesis that all family members contain a structurally related ATP binding site that binds wortmannin in a similar position, and that the substrate-binding site of PI3K and PI4K is structurally related to each other, whereas the substrate-binding site of the PIKKs is unrelated.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 磷酸肌醇激酶相关的蛋白激酶（PIKK）MTOR，ATM和ATR具有 关键的细胞功能。 MTOR是PI3K/AKT信号传导中的中央效应子激酶 在人类癌症中经常失调的途径。 ATM和ATR是必不可少的 DNA损伤信号通路中的细胞周期检查点激酶，保护细胞 针对DNA损伤和氧化应激。 针对MTOR的抑制剂目前正在 临床癌症治疗试验。针对这些酶的其他选择性抑制剂可能 在实验室实验中有许多应用，可能具有临床价值 癌症的治疗。 MTOR，ATM和ATR是具有分子量的大蛋白 分别为288、350和300KDA。它们包含一个保守的C末端区域， 由脂肪结构域，催化Pikk蛋白激酶结构域和FATC结构域组成。 所有三种蛋白的催化结构域与 磷酸肌醇激酶（PIK），例如磷脂酰肌醇3和4激酶（PI3K，， PI4K）。小分子抑制剂抑制所有PIK和PIKK催化域 Wortmannin，与ATP结合位点结合。尽管功能很重要 Pikks，目前只有一种I类PI3K的蛋白质结构作为模板 这个酶家族。 在这里，我们建议确定X射线晶体结构 PIK和PIKKS的催化结构域研究酶促的结构基础 催化和底物特异性。我们将检验所有家庭成员的假设 包含一个与结构相关的ATP结合位点，该结合位点在类似 位置，PI3K和PI4K的底物结合位点在结构上与 彼此，而派克的底物结合位点是无关的。