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Structural and Bioinformatics Analyses of M1 Aminopeptidases

M1 氨基肽酶的结构和生物信息学分析

基本信息

批准号：
10437967
负责人：
Hwai-Chen Guo
金额：
$ 45.59万
依托单位：
UNIVERSITY OF MASSACHUSETTS LOWELL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437967
关键词：
Alzheimer&apos s Disease Aminopeptidase Antigens Autoimmunity Binding Binding Sites Biochemical Bioinformatics Biological Assay Biophysics C-terminal Catalytic Domain Cell Maintenance Cellular Immunity Chronic Disease Communicable Diseases Complex Crystallization Development Disease Distal Docking Endoplasmic Reticulum Environment Enzymes Family Family member Hand Human Hypertension Immune In Vitro Insulin Knowledge Lead Libraries Ligands Major Histocompatibility Complex Malaria Malignant Neoplasms Molecular Mutation Analysis Parkinson Disease Peptide Hydrolases Peptides Periodicity Play Public Health Research Site Specificity Structure Substrate Specificity Testing Therapeutic Ubenimex Universities Validation Virus Diseases X-Ray Crystallography analog base combinatorial comparative design fight against graduate student human disease improved in silico inhibitor insight member metalloenzyme novel pathogen peptide structure pharmacophore preference screening side effect small molecule therapeutic target undergraduate research experience undergraduate student

项目摘要

Project Summary Endoplasmic reticulum aminopeptidase 1 (ERAP1) and insulin-regulated aminopeptidase (IRAP) belong to the oxytocinase subfamily of M1 aminopeptidases (M1APs), which are a diverse family of metalloenzymes involved in a wide range of functions including cell maintenance, development, and immune defense, and have been implicated in various chronic and infectious diseases of humans. Structure and mechanism of the conserved catalytic domain, termed peptidase_M1 domain, have been well studied. As a result, many research groups have begun assessing their potential as therapeutic targets for various diseases, such as cancer, autoimmunity, Alzheimer's and Parkinson's diseases, hypertension, and viral infections. However, targeting any M1AP to treat human diseases is complicated because there are nine characterized and closely related M1APs in humans. This poses a dilemma situation to deal with off-target side effects. Nonetheless, current inhibitor- developing strategies rely heavily on Bestatin derivatives or phosphinic pseudopeptides to occupy the S1 and/or S1’ binding pockets of the highly conserved peptidase_M1 site. Although potent, these inhibitors also inhibit many other essential M1AP members, lead to undesired side effects. Our lab has previously determined a novel ERAP1 C-terminal regulatory domain structure, now classified as the ERAP1_C like domain. This ERAP1_C fold, separated from the conserved peptidase_M1 domain, is found in all available structures of the M1AP family, but their sequences vary substantially among family members, likely to harbor distinct specificity subsites. Indeed, our recent results on four structures of ERAP1_C domain in complex with various substrate C-termini have revealed specificity subsites (e.g., SC’ subsite) embedded in this ERAP1_C domain to recognize ERAP1- specific anchor residue at the substrate carboxyl-end, a critical feature of ERAP1 to act as a molecular ruler in generating antigens with a correct size. We thus hypothesize that each M1AP carries distinct specificity subsites in its special version of ERAP1_C domain to accommodate distal parts of their cognate substrates. To test this hypothesis, we propose in this R15 project to investigate structural details of IRAP specificity subsites for recognizing the distal ends of its cognate substrates, and to exploit newly identified specificity subsites for targeted screenings to identify modulators that are both potent and selective against ERAP1 or IRAP over other M1APs. The proposed research will provide insights into both common and distinct interactions between specificity subsites of different M1APs and their cognate substrates, and is thus critical to improve our capability to develop specific and selective modulators or inhibitors to fight against pathogens or chronic diseases. Furthermore, this AREA research will provide continuous research opportunities for undergraduate and graduate students at UMass Lowell, and help the University to enhance its research environment.

项目摘要内质网氨肽酶1（ERAP 1）和胰岛素调节氨肽酶（IRAP）属于 M1氨基肽酶（M1APs）催产素酶亚家族，是一个不同的金属酶家族参与广泛的功能，包括细胞维持，发育和免疫防御，并具有与人类的各种慢性和传染病有关。结构和机制保守的催化结构域，称为肽酶_M1结构域，已经被很好地研究。因此，许多研究研究小组已经开始评估它们作为各种疾病，如癌症，自身免疫、阿尔茨海默病和帕金森病、高血压和病毒感染。然而，针对任何 M1AP治疗人类疾病是复杂的，因为有九个特征性的和密切相关的M1AP 在人类身上。这造成了处理脱靶副作用的两难境地。尽管如此，目前的抑制剂- 开发策略严重依赖于Bestatin衍生物或次膦酸假肽来占据S1和/或高度保守的肽酶_M1位点的S1'结合口袋。尽管这些抑制剂很有效，许多其他重要的M1AP成员，导致不希望的副作用。我们的实验室之前确定了一本小说 ERAP 1 C-末端调控结构域结构，现在被归类为ERAP 1_C样结构域。此ERAP 1_C 折叠，与保守的肽酶_M1结构域分离，存在于M1AP家族的所有可用结构中，但它们的序列在家族成员中有很大的差异，可能具有不同的特异性亚位点。事实上，我们最近关于ERAP 1_C结构域与各种底物C-末端复合的四种结构的结果，已经揭示了特异性亚位点（例如，SC’子位点）以识别ERAP 1-C。在底物羧基端的特定锚残基，ERAP 1的一个关键特征，作为一个分子标尺，产生具有正确大小的抗原。因此，我们假设每个M1AP携带不同的特异性亚位点在其ERAP 1_C结构域的特殊形式中，以容纳其同源底物的远端部分。为了验证这一假设，我们建议在这个R15项目中研究IRAP特异性亚位点的结构细节，识别其同源底物的远端，并利用新鉴定的特异性亚位点，靶向筛选以鉴定相对于其他调节剂对ERAP 1或IRAP既有效又有选择性的调节剂。 M1AP。拟议的研究将提供对共同和独特的相互作用的见解，不同M1AP及其同源底物的特异性亚位点，因此对于提高我们的能力至关重要开发特异性和选择性调节剂或抑制剂，以对抗病原体或慢性疾病。此外，该领域的研究将为本科生和研究生提供持续的研究机会学生在麻省大学洛厄尔分校，并帮助大学，以提高其研究环境。