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：
9128445
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
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/9128445
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 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 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 small molecule inhibitor 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（HER）激活和信号传导的基本机制进行分子和结构理解。 HER 受体酪氨酸激酶、EGFR、HER2、HER3 和 HER4 在控制细胞生长、存活和运动方面发挥着关键作用。这些受体的失调在不同类型的癌症、神经病理性疾病和心血管疾病中很常见。虽然过去十年在识别靶向 EGFR 和 HER2 的药物方面取得了重大进展，但 HER3 受体介导的耐药性的发展是一个新出现的问题。 HER3 是 HER 家族中一个不寻常的成员，因为它没有催化活性。然而，它可以与 EGFR 和 HER2 形成二聚体，导致其催化结构域变构激活。 HER3 是药物发现的一个具有挑战性的靶标，因为它缺乏酶活性位点，而且我们不太了解 HER3 如何与 EGFR 和 HER2 相互作用。该申请将通过定义 HER3 与 EGFR 和 HER2 形成活性信号复合物的分子机制来解决这些问题，并探索这些知识来开发 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，这是根据我们的初步数据提出的假设，并且了解 HER3 与其他 HER 异二聚化的分子基础将揭示 HER3 的基本原理变构功能。将研究以下具体目标： 1. 研究核苷酸结合调节 HER3 变构功能的机制，以了解抑制 HER3 的小分子的产生； 2. 将研究 HER3 与 EGFR 和 HER2 异二聚化的结构基础，以确定生长因子结合与催化激活在结构上耦合的机制； 3. 将使用单分子成像研究 HER3 异二聚化对细胞中 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，并将定义 HER3 对其他 HER 受体的变构功能的未知方面。这项工作还将有助于开发新颖的实验策略，旨在克服与研究膜受体相关的挑战。这项研究意义重大，因为它为 HER 受体家族的激活机制增加了一个新的调控步骤。此外，拟议的研究有望促进我们对 HER 受体如何整合外部激活信号以严格控制其细胞内酶功能的激活的分子理解。最终，对 HER3 功能的详细了解将为下一代抑制剂的开发提供信息，这些抑制剂有助于缓解人类疾病中针对 HER 受体的药物日益严重的耐药性问题。