Mechanism of allosteric signal integration in Src tyrosine kinase

Src酪氨酸激酶变构信号整合机制

• 批准号: 8867868
• 负责人: Zachariah Hussein Foda
• 金额: $ 4.64万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867868
• 关键词: Active Sites; Affinity; Allosteric Site; Amino Acids; Animal Model; Apoptosis; Binding; Binding Sites; Biochemical; Biological Assay; Catalytic Domain; Cell Cycle; Cell Death; Cell Survival; Cell physiology; Cells; Cellular Assay; Chronic; Clinical; Computer Simulation; Cyclic AMP-Dependent Protein Kinases; Cyclins; Data; Development; Diabetes Mellitus; Disease; Distant; Docking; Drug Targeting; Drug resistance; Enzymes; Family; Future; Gastrointestinal Stromal Tumors; Goals; Growth; Human; Imatinib; Individual; Laboratories; Length; Ligand Binding; Ligands; Link; Lobe; Lytic; Malignant Neoplasms; Molecular; Mutation; Myelogenous; Neoplasm Metastasis; PDGFRB gene; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Physiological; Post-Translational Protein Processing; Prevalence; Process; Property; Protein Kinase; Protein Tyrosine Kinase; Proteins; Proto-Oncogenes; Regulation; Resistance; Route; Signal Transduction; Site; Specificity; Therapeutic; Therapeutic Intervention; Tissues; Translating; Work; angiogenesis; base; biological adaptation to stress; cell motility; clinically relevant; inhibitor/antagonist; kinase inhibitor; member; molecular dynamics; novel; novel therapeutics; prevent; public health relevance; research study; simulation; small molecule; small molecule libraries; src-Family Kinases; therapeutic target; tumor progression

DESCRIPTION (provided by applicant): Protein kinases, as key cellular pathway regulators, are frequently linked to disease and provide opportunities for therapeutic intervention. Due to their prevalence and importance, strict regulation of kinase activity is necessary to control essential cellular processes including the cell cycle, proliferation, differentiation, motility, an cell death or survival. Small molecule kinase inhibitors selected for their ability to target the kinase ATP-binding pocket have achieved clinical utility. However, the high sequence and structural conservation of the pocket found in the more than 500 human protein kinases has created a challenge to developing inhibitors specific for individual kinases. Many limitations in using these small molecule inhibitors derive from their cross-inhibition of other kinases unconnected to the targeted disease process. Part of the mechanism through which protein kinases achieve precise regulation, though, involves integration of many inter- and intramolecular signals via sites that are considerably less well conserved in sequence and function. These non-conserved mechanisms of regulation therefore provide the opportunity for more precise therapeutic targeting, for example, through the development of allosteric inhibitors based on high-affinity and high-specificity ligands. However, it is challenging to identify such allosteric sites in detai. Recently, my sponsor's laboratory identified a previously unknown allosteric network of amino acids that spans the length of the kinase and may thus facilitate integration of allosteric signals into the regulation of protein kinase catalytic domain activity. I propose to experimentally probe the allosteric network and identify ligands that stabilize a predicted allosteric pocket. The findings from this work will deepen our understanding of the fundamental regulatory mechanisms for this important class of drug targets and potentially open the way to the development of more specific therapeutics.

描述（由申请人提供）：蛋白激酶作为关键的细胞途径调节剂，经常与疾病相关并为治疗干预提供机会。由于其普遍性和重要性，对激酶活性的严格调节对于控制重要的细胞过程是必要的，包括细胞周期、增殖、分化、运动、细胞死亡或存活。因其靶向激酶的能力而被选择的小分子激酶抑制剂 ATP结合口袋已实现临床应用。然而，在 500 多种人类蛋白激酶中发现的口袋的高度序列和结构保守性给开发针对单个激酶的特异性抑制剂带来了挑战。使用这些方法有很多限制 小分子抑制剂源自对与目标疾病过程无关的其他激酶的交叉抑制。然而，蛋白激酶实现精确调节的部分机制涉及通过序列和功能保守性相当差的位点整合许多分子间和分子内信号。因此，这些非保守的调节机制为更精确的治疗靶向提供了机会，例如通过开发基于高亲和力和高特异性配体的变构抑制剂。然而，详细识别此类变构位点具有挑战性。最近，我的资助者的实验室发现了一种以前未知的氨基酸变构网络，该网络跨越激酶的长度，因此可能促进变构信号的整合 参与蛋白激酶催化结构域活性的调节。我建议通过实验探测变构网络并识别稳定预测变构袋的配体。这项工作的结果将加深我们对这类重要药物靶点的基本调控机制的理解，并有可能为开发更具体的治疗方法开辟道路。