Structural and Functional Studies of HER Receptor Tyrosine Kinases

HER 受体酪氨酸激酶的结构和功能研究

• 批准号: 8911844
• 负责人: Natalia Jura
• 金额: $ 29.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8911844
• 关键词: ATP Hydrolysis; Activator Appliances; Active Sites; Address; Affect; Allosteric Regulation; Architecture; Binding; Binding Sites; Biological Assay; Cardiovascular Diseases; Catalytic Domain; Cell membrane; Cells; Complex; Coupled; Crystallization; Data; Detergents; Development; Dimerization; Disease; Dissection; Drug Targeting; Drug resistance; ERBB2 gene; Electron Microscopy; Environment; Epidermal Growth Factor Receptor; ErbB4 gene; Extracellular Domain; Family; Fluorescence; Future; Generations; Goals; Growth Factor; Health; Heterodimerization; Homeostasis; Homologous Gene; Human; Human Activities; Image; In Vitro; Investigation; Knowledge; Label; Length; Ligand Binding; Ligands; Link; Lipids; Mediating; Membrane; Microscopy; Molecular; Mutagenesis; Mutation; Nucleotides; Optics; Phosphotransferases; Play; Process; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Relative (related person); Research; Resistance; Resistance development; Resolution; Role; Signal Pathway; Signal Transduction; Structural Models; Structure; Testing; Work; X-Ray Crystallography; base; cancer therapy; cancer type; cell growth; cell motility; combat; design; dimer; driving force; drug discovery; human disease; inhibitor/antagonist; innovation; insight; interdisciplinary approach; kinase inhibitor; member; molecular dynamics; nanodisk; next generation; novel; receptor; receptor function; reconstitution; reconstruction; response; scaffold; single molecule; small molecule; tool

DESCRIPTION (provided by applicant): The long-term goals of this project are to develop a molecular and structural understanding of the fundamental mechanisms that control activation and signaling by human epidermal growth factor receptors (HERs). HER receptor tyrosine kinases, EGFR, HER2, HER3 and HER4 play pivotal roles in controlling cellular growth, survival and motility. Misregulation of these receptors is common in different types of cancer, neuropathological disorders and cardiovascular diseases. While significant progress has been made in identifying drugs that target EGFR and HER2 over the past decade, the development of resistance mediated by the HER3 receptor is an emerging problem. HER3 is an unusual member of the HER family, because it is catalytically inactive. It can, however, dimerize with EGFR and HER2 resulting in the allosteric activation of their catalytic domains. HER3 is a challenging target for drug discovery because it lacks an enzymatically active site and we do not understand very well how HER3 interacts with EGFR and HER2. This application will address these issues by defining the molecular mechanism by which HER3 forms active signaling complexes with EGFR and HER2, and exploring this knowledge to develop HER3 inhibitors. The central hypotheses are that allosteric function of HER3 can be modulated through its nucleotide-binding site, which is a hypothesis formulated based on our preliminary data, and that an understanding of the molecular underpinnings of HER3 heterodimerization with other HERs will reveal basic principles of HER3 allosteric function. The following specific aims will be investigated: 1. The mechanism by which nucleotide binding regulates allosteric function of HER3 will be studied to inform the generation of small molecules that inhibit HER3; 2. The structural basis for HER3 heterodimerization with EGFR and HER2 will be investigated to define the mechanism by which growth factor binding is structurally coupled to catalytic activation; 3. The contribution of HER3 heterodimerization to signaling by EGFR and HER2 in cells will be investigated using single molecule imaging. This approach is innovative because it addresses a novel functionality within HER3 and will define the unknown aspects of HER3 allosteric function towards other HER receptors. This work will also contribute to the development of novel experimental strategies designed to overcome the challenges associated with studying membrane receptors. The proposed research is significant because it adds a new regulatory step in the activation mechanism of the HER family of receptors. Moreover, the proposed research is expected to advance our molecular understanding of how HER receptors integrate external activating signals to result in tightly controlled activation of their intracellular enzymtic functions. Ultimately, this detailed understanding of HER3 functions will inform the development of next generation inhibitors that can help alleviate the increasing problem of resistance to agents that target HER receptors in human diseases.

描述（由申请人提供）：本项目的长期目标是从分子和结构上了解控制人表皮生长因子受体（HER）激活和信号传导的基本机制。HER受体酪氨酸激酶EGFR、HER 2、HER 3和HER 4在控制细胞生长、存活和运动中起关键作用。这些受体的失调常见于不同类型的癌症、神经病理性疾病和心血管疾病。虽然在过去的十年中，在鉴定靶向EGFR和HER 2的药物方面取得了重大进展，但由HER 3受体介导的耐药性的发展是一个新出现的问题。HER 3是HER家族的一个不寻常的成员，因为它是催化失活的。然而，它可以与EGFR和HER 2二聚化，导致其催化结构域的变构活化。HER 3是药物发现的一个具有挑战性的靶点，因为它缺乏酶活性位点，我们不太了解HER 3如何与EGFR和HER 2相互作用。本申请将通过定义HER 3与EGFR和HER 2形成活性信号传导复合物的分子机制，并探索开发HER 3抑制剂的知识来解决这些问题。中心假设是HER 3的变构功能可以通过其核苷酸结合位点调节，这是基于我们的初步数据制定的假设，并且理解HER 3与其他HER异源二聚化的分子基础将揭示HER 3变构功能的基本原理。以下具体目标将被调查：1。将研究核苷酸结合调节HER 3变构功能的机制，以告知抑制HER 3的小分子的产生; 2.将研究HER 3与EGFR和HER 2异源二聚化的结构基础，以确定生长因子结合在结构上与催化活化偶联的机制; 3.将使用单分子成像研究HER 3异二聚化对细胞中EGFR和HER 2信号传导的贡献。这种方法是创新的，因为它解决了HER 3内的新功能，并将定义HER 3对其他HER受体的变构功能的未知方面。这项工作也将有助于开发新的实验策略，旨在克服与研究膜受体相关的挑战。这项研究意义重大，因为它在HER受体家族的激活机制中增加了一个新的调节步骤。此外，拟议的研究有望推进我们对HER受体如何整合外部激活信号以导致其细胞内酶功能的严格控制激活的分子理解。最终，对HER 3功能的详细了解将为下一代抑制剂的开发提供信息，这些抑制剂可以帮助缓解人类疾病中靶向HER受体的药物耐药性日益增加的问题。