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

基本信息

批准号：
9330160
负责人：
Natalia Jura
金额：
$ 44.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/9330160
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 Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ErbB4 gene Extracellular Domain Family Fluorescence Future Generations Goals Growth Factor Heterodimerization Homeostasis Human In Vitro Investigation Knowledge Label Length Ligand Binding Ligands Link Lipids Mediating Membrane Microscopy Molecular Mutagenesis Mutation Nucleotides Optics Pathologic Phosphotransferases Play Process Receptor Protein-Tyrosine Kinases Receptor Signaling Regulation 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 molecular imaging nanodisk next generation novel public health relevance receptor receptor function reconstitution reconstruction response scaffold single molecule small molecule small molecule inhibitor spatiotemporal targeted agent tool

项目摘要

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）：该项目的长期目标是对控制人类表皮生长因子受体（HERS）控制激活和信号传导的基本机制的分子和结构理解。她的受体酪氨酸激酶，EGFR，HER2，HER3和HER4在控制细胞生长，生存和运动中扮演着关键的角色。这些受体的不调节在不同类型的癌症，神经病理学疾病和心血管疾病中很常见。尽管在过去十年中，在识别靶向EGFR和HER2的药物方面取得了重大进展，但HER3受体介导的抗药性的发展是一个新的问题。 Her3是她家人的不寻常成员，因为它是催化性的。但是，它可以用EGFR和HER2二聚，从而导致其催化域的变构激活。 HER3是吸毒发现的挑战性目标，因为它缺乏酶促活跃的网站，我们不太了解Her3如何与EGFR和HER2相互作用。该应用将通过定义HER3与EGFR和HER2形成主动信号复合物的分子机制来解决这些问题，并探索这些知识以开发HER3抑制剂。中心假设是，HER3的变构功能可以通过其核苷酸结合位点进行调节，这是基于我们的初步数据提出的假设，并且对HER3 HER3异构二聚体的分子基础的理解将揭示Her3 Alstrosteric Alterstoric函数的基本原理。将研究以下特定目标：1。将研究核苷酸结合调节HER3的变构功能的机制，以告知抑制HER3的小分子的产生。 2。将研究HER3异二聚体和HER2的结构基础，以定义生长因子结合在结构上与催化活化的结合的机制； 3。将使用单分子成像研究HER3异二二聚化对EGFR和HER2信号传导的贡献。这种方法具有创新性，因为它解决了HER3内的新功能，并将将HER3变构功能的未知方面定义为其他受体。这项工作还将有助于发展新型实验策略，旨在克服与研究膜受体相关的挑战。拟议的研究很重要，因为它在她的受体家族的激活机制中增加了新的调节步骤。此外，预计拟议的研究将促进我们对她的受体如何整合外部激活信号的分子理解，从而导致其细胞内酶功能的严格控制。最终，对HER3功能的详细理解将为下一代抑制剂的发展提供信息，这些抑制剂可以帮助减轻针对其受体在人类疾病中的受体的耐药性问题。