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Project 3: Structural Basis for grp94 Drug Development and Chaperone Function

项目3：grp94药物开发和伴侣功能的结构基础

基本信息

批准号：
8934515
负责人：
DANIEL T GEWIRTH
金额：
$ 34.71万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8934515
关键词：
ATP Hydrolysis Address Adverse effects Affinity Amino Acids Binding Biochemical Cancer Biology Cells Chemicals Cleaved cell Client Collaborations Complex Data Development Drug Design Elements Endoplasmic Reticulum Exhibits Family Fostering Generations Goals Heat-Shock Proteins 90 In Vitro Individual Knowledge Lead Ligands Malignant Neoplasms Metabolic Modification Molecular Chaperones Molecular Conformation N Domain N-terminal Oncogenic Play Post-Translational Modification Site Post-Translational Protein Processing Property Proteins Purines Role Route Site Structure Testing Therapeutic Thermodynamics Work anti-cancer therapeutic base cancer therapy design drug development glycosylation improved in vivo inhibitor/antagonist mutant next generation novel novel therapeutics paralogous gene purine research study response three dimensional structure

项目摘要

PROJECT SUMMARY Grp94 is an ER HSP90 chaperone whose broad oncogenic roles have only recently been established. However, understanding of grp94 structure and mechanism has lagged behind that of other HSP90s. grp94 exhibits high sequence and structural homology to the other cellular HSP90 paralogs. Nevertheless, attempts to demonstrate complementation between the cytosolic and ER paralogs have consistently failed in both directions, suggesting that the enormous metabolic burden of maintaining high levels of a specialized ER- specific HSP90 has a distinct mechanistic purpose. We propose that this distinct mechanism is reflected in its structure. The goal of this project is to understand what makes grp94 unique in the HSP90 family and to exploit these features in the design of new inhibitors as cancer therapeutics. We will address this question in four specific aims. The first is to characterize and develop next-generation grp94-selective inhibitors. Together with Dr. Gabriela Chiosis, leader of Project 2, we have characterized a set of purine-based (PU) compounds that bind selectively to grp94 and exhibit anti-cancer activity. Higher affinity and more selective compounds are needed to improve their therapeutic potential and to serve as chemical probes of grp94 function. The second is to determine the structural basis for selective binding of PU ligands to grp94. We will investigate how the conformational changes in grp94 that foster selective inhibitor binding manage to occur in one paralog and not another – what specific sequence and structural elements make the grp94 response distinct? Third, we aim to determine how individual structural domains contribute to the unique biochemical and functional properties of grp94. In collaboration with Dr. Zihai Li, leader of Project 1, we will examine how individual grp94 domains contribute to the overall specialization and function of this paralog as it matures its client proteins such as GARP. Fourth, we will probe the role of post-translational modifications (PTMs) on grp94 client binding and activity. Together these experiments should pave the way for the development of new anti-cancer therapeutics and illuminate central mechanistic questions about grp94 action.

项目概要 Grp94 是一种 ER HSP90 伴侣，其广泛的致癌作用最近才被确定。然而，对grp94结构和机制的了解却落后于其他HSP90。组94 与其他细胞 HSP90 旁系同源物表现出高度的序列和结构同源性。尽管如此，尝试证明胞质和 ER 旁系同源物之间的互补在这两种情况下始终失败方向，表明维持高水平的专门 ER- 的巨大代谢负担特定的 HSP90 具有独特的机制目的。我们建议这种独特的机制体现在结构。该项目的目标是了解 grp94 在 HSP90 系列中的独特之处并利用这些特点体现在设计新抑制剂作为癌症治疗药物中。这个问题我们分四步来解答具体目标。第一个是表征和开发下一代 grp94 选择性抑制剂。连同项目 2 的负责人 Gabriela Chiosis 博士，我们鉴定了一组嘌呤基 (PU) 化合物，选择性结合 grp94 并表现出抗癌活性。更高亲和力和更具选择性的化合物需要提高其治疗潜力并作为 grp94 功能的化学探针。第二个是确定 PU 配体选择性结合 grp94 的结构基础。我们将调查如何 grp94 中促进选择性抑制剂结合的构象变化设法发生在一个旁系同源物中，而不是发生在另一个 – 哪些特定的序列和结构元素使 grp94 反应与众不同？第三，我们的目标是确定各个结构域如何有助于独特的生化和功能特性 grp94。我们将与项目 1 的负责人李子海博士合作，研究各个 grp94 域如何随着该旁系同源物成熟其客户蛋白，例如，有助于该旁系同源物的整体专业化和功能盖普。第四，我们将探讨翻译后修饰 (PTM) 对 grp94 客户端结合和活动。这些实验应该为新的抗癌疗法的开发铺平道路并阐明有关 grp94 行动的核心机制问题。