Structure and functional mechanisms of molecular chaperones and protein kinases

分子伴侣和蛋白激酶的结构和功能机制

• 批准号: 9920188
• 负责人: CHARALAMPOS KALODIMOS
• 金额: $ 75.38万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920188
• 关键词: Actins; Address; Affinity; Architecture; BCR/ABL fusion gene; Biochemical; Biological Process; Cell Adhesion; Cells; Chimeric Proteins; Chronic Myeloid Leukemia; Client; Complex; DNA Damage; Drug resistance; Human Genome; Mediating; Molecular Chaperones; Molecular Structure; NMR Spectroscopy; Pharmaceutical Preparations; Phosphotransferases; Protein Dynamics; Protein Family; Protein Kinase; Protein Tyrosine Kinase; Proteins; Proteome; Reporting; Resolution; Role; Structure; Therapeutic Intervention; Work; biophysical techniques; cell motility; fascinate; gene product; non-Native; novel; pathogenic bacteria; protein aggregation; resistance mutation; response; targeted treatment

PROJECT SUMMARY Our lab works on two main directions: first, the determination of the structural and dynamic basis for the function and assembly of large protein machineries; and second, the determination of the role of internal protein dynamics in regulating protein activity and allosteric interactions. We propose to use NMR spectroscopy, together with other biochemical and biophysical techniques, to determine at the atomic resolution the mechanisms underpinning the function of two important protein families: molecular chaperones and protein kinases. Molecular chaperones are central to maintaining a functional proteome in the cell by rescuing non- native proteins from aggregation and misfolding and assisting with their folding. Our lab reported the first ever high resolution structures of molecular chaperones in complex with unfolded proteins. We will determine the structures of important chaperones such as the Hsp40, Hsp70 and Hsp90 in complex with client proteins. We wish to address how different chaperones engage non-native proteins and how distinct chaperone architectures may alter activity. The Abl kinase holds a prominent place among the over 500 protein kinases encoded by the human genome. Abl mediates its function by participating in a number of biological processes, including actin remodeling, cell adhesion and motility, DNA damage response, and bacterial pathogen response. The Bcr-Abl fusion gene product has constitutive tyrosine kinase activity and causes chronic myeloid leukemia (CML). We will use NMR to provide fascinating, novel information about the regulatory and activation mechanisms of this important kinase. We will study how drug-resistance mutations exert their effect in lowering the drug affinity for Abl.

项目摘要 我们的实验室工作在两个主要方向：第一，确定结构和动态基础， 大型蛋白质机器的功能和组装;第二， 调节蛋白质活性和变构相互作用的内部蛋白质动力学。我们建议使用 NMR光谱法，连同其他生物化学和生物物理技术，以确定在 原子分辨率支持两个重要蛋白质家族功能的机制： 分子伴侣和蛋白激酶。 分子伴侣是维持细胞中功能蛋白质组的核心， 天然蛋白质聚集和错误折叠，并协助其折叠。我们的实验室报告说 第一个高分辨率的分子伴侣结构与未折叠蛋白质的复合物。我们 将确定重要的分子伴侣的结构，如Hsp 40，Hsp 70和Hsp 90， 与客户蛋白质的复合物。我们希望解决不同的伴侣如何参与非本地 蛋白质以及不同的分子伴侣结构如何改变活性。 Abl激酶在由人类基因编码的超过500种蛋白激酶中占有突出的位置。 基因组Abl通过参与许多生物过程来介导其功能，包括 肌动蛋白重塑、细胞粘附和运动、DNA损伤反应和细菌病原体 反应Bcr-Abl融合基因产物具有组成型酪氨酸激酶活性，并引起慢性炎症。 骨髓性白血病（CML）。我们将使用核磁共振提供迷人的，新颖的信息， 这一重要激酶的调节和激活机制。我们将研究抗药性 突变在降低对药物的依赖性方面发挥作用。