SRC, A PROTEIN KINASE ACTIVE IN CHRONIC MYELOID LEUKEMIA

SRC，一种在慢性粒细胞白血病中活跃的蛋白激酶

• 批准号: 8363361
• 负责人: Markus A Seeliger
• 金额: $ 0.21万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363361
• 关键词: Address; Affect; Binding; Biochemical; Biological Assay; Cell division; Chimeric Proteins; Chronic Myeloid Leukemia; Clinical; Complex; Crystallography; Cyclic AMP-Dependent Protein Kinases; Disease; Drug Delivery Systems; Drug resistance; Elements; Energy Metabolism; Event; Funding; Gleevec; Goals; Grant; Imatinib; Kinetics; Ligand Binding; Light; Mediating; Molecular Conformation; Motion; National Center for Research Resources; Nuclear Magnetic Resonance; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Principal Investigator; Process; Protein Kinase; Proteins; Proto-Oncogenes; Regulation; Research; Research Infrastructure; Resources; Roentgen Rays; Role; Signal Transduction; Source; Specificity; Structure; Synchrotrons; United States National Institutes of Health; Vertebral column; cost; flexibility; inhibitor/antagonist; kinase inhibitor; research study; resistance mutation; src-Family Kinases; success

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Protein kinases mediate many cell signaling events, and their tight control is essential for regulating vital processes ranging from cell division to energy metabolism. Thus, it is not surprising that protein kinases are directly or indirectly involved in many diseases and that kinases are key drug targets. For example, Src kinase was the first identified proto-oncogene and the formation of a de-regulated Abl fusion protein (BCRAbl) is the cause of disease in 95% of patients with chronic myeloid leukemia. X-ray crystal structures have shown that the same kinases can attain an active and various inactive conformations, implying that kinases are inherently flexible. How the active and inactive states are stabilized and how these states interconvert are key questions in understanding kinase regulation. Because X-ray crystal structures provide only static snapshots, we will use nuclear magnetic resonance (NMR) experiments and ligand binding kinetics to study the timescales and amplitudes of structural interconversions in Abl and Src kinase domains. BCR-Abl is the target of the clinically highly successful drug imatinib (Gleevec¿, Novartis) in the treatment of chronic myelogenous leukemia (CML). The clinical success of imatinib is due to its excellent specificity, binding only to the inactive conformation of the kinase. Therefore drug binding is intimately related to the interconversion between active and inactive states. The goal of this study is to examine timescales and pathways of these interconversions between active and inactive conformations, how dynamics of structural elements relate to catalytic turnover of the kinase and how drug resistance mutations affect these dynamics. Therefore, we will compare the timescales and amplitudes of backbone motions between Src and Abl kinases in the presence of drugs by NMR experiments. Ligand binding kinetics will be used to address the role of the regulatory domains on kinase dynamics and the binding mechanisms of different classes of kinase inhibitors. The role of protein plasticity and dynamics on inhibitor promiscuity will be addressed by structural studies on kinase+inhibitor complexes, inhibitor binding kinetics and biochemical assays.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 蛋白激酶介导许多细胞信号事件，其严格控制对于控制从细胞分裂到能量代谢的重要过程至关重要。这是毫不奇怪的是，蛋白激酶直接或间接地参与许多疾病，而激酶是关键的药物靶标。例如，SRC激酶是首次鉴定出的原始癌基因，并且在95％的慢性骨髓性白血病患者中，造成95％的疾病的原因是疾病的原因。 X射线晶体结构表明，相同的激酶可以达到活跃和各种非活动构象，这意味着激酶本质上是柔性的。主动状态和非活动状态如何稳定以及这些状态如何互连是理解激酶调节的关键问题。由于X射线晶体结构仅提供静态快照，因此我们将使用核磁共振（NMR）实验和配体结合动力学来研究ABL和SRC激酶结构域中结构相互转换的时标和放大器。 BCR-ABL是临床上非常成功的药物伊马替尼（Gleevec。，诺华）的靶标，以治疗慢性骨髓性白血病（CML）。伊马替尼的临床成功归因于其出色的特异性，仅与激酶的无活性构型结合。因此，药物结合与活性状态和非活性状态之间的互连密切相关。 这项研究的目的是检查活动和非活动构象之间这些相互转换的时间尺度和途径，结构元素的动力学与激酶的催化转化以及耐药性突变如何影响这些动力学有关。因此，我们将在NMR实验存在药物的情况下比较SRC和ABL激酶之间主链运动的时间标度和放大器。配体结合动力学将用于解决调节域对激酶动力学的作用以及不同类别的激酶抑制剂的结合机制。蛋白质可塑性和动力学对抑制剂杂交的作用将通过有关激酶+抑制剂复合物，抑制剂结合动力学和生化测定的结构研究来解决。