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Structural Analysis of a Virulence Gene Regulator in Chlamydia

衣原体毒力基因调节因子的结构分析

基本信息

批准号：
7849909
负责人：
P Scott Hefty
金额：
$ 7万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2012-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Chlamydiae infections have an immense impact of public health causing sterility, blindness, pneumonia, and correlated with formation of atherosclerotic lesions and heart disease. These obligate intracellular bacteria are perpetuated through a developmental cycle that is intimately linked to pathogenesis. There is a critical deficiency in our understanding of the factors and mechanisms that control the development cycle and pathogenesis; however, transcriptional regulation has a governing role in chlamydial development. Elucidating transcriptional regulatory factors and mechanisms employed is central to understanding chlamydial development and pathogenesis, defining virulence determinants, and identifying novel targets for future disease intervention strategies. The long-term goal of our research is to characterize the molecular mechanisms that regulate chlamydial development and pathogenesis. This proposal is designed to gain structural information of a chlamydial transcription factor, ChxR, which is important for chlamydial development and pathogenesis. ChxR is a 26 kD protein homologous to the well-studied and widespread OmpR subfamily of two-component signal transduction response regulators. Our central hypothesis is that native ChxR is maintained in a structural conformation that corresponds to the transient active state of the phosphorylated OmpR response regulators. To generate critical preliminary data for eventual testing the stated hypothesis, we propose two Specific Aims; 1) Determine the three-dimensional crystal structure of intact full-length ChxR response regulator and 2) Determine ChxR receiver-effector domain interface. As a result of the proposed studies, regions and residues requisite for transcriptional regulation will be identified allowing future functional studies to elucidate the precise regulatory mechanism of ChxR. PUBLIC HEALTH RELEVANCE: Proposed studies will facilitate our understanding of how and what controls development and disease for the medically important bacteria, Chlamydia. Furthermore, response regulators such as the one in this study are widespread in bacteria and absent in mammals and as such, are attractive targets for development of new antimicrobials.

描述（由申请人提供）：衣原体感染对公共卫生有巨大影响，可导致不育、失明、肺炎，并与动脉粥样硬化病变和心脏病的形成相关。这些专性细胞内细菌通过与发病机制密切相关的发育周期而永久存在。有一个关键的缺陷，我们的理解的因素和机制，控制的发展周期和发病机制，然而，转录调控衣原体的发展具有主导作用。阐明转录调控因子和机制的核心是了解衣原体的发展和发病机制，定义毒力决定因素，并确定新的目标，为未来的疾病干预策略。我们的研究的长期目标是表征调控衣原体发育和发病机制的分子机制。该提案旨在获得衣原体转录因子ChxR的结构信息，ChxR对衣原体的发展和发病机制非常重要。ChxR是一个26 kD的蛋白质同源的研究和广泛的OmpR亚家族的双组分信号转导反应调节剂。我们的中心假设是，天然ChxR保持在一个结构构象，对应于磷酸化OmpR反应调节剂的瞬时活性状态。为了生成用于最终测试所述假设的关键初步数据，我们提出了两个具体目标：1）确定完整全长ChxR反应调节剂的三维晶体结构和2）确定ChxR受体-效应器结构域界面。作为拟议的研究的结果，区域和残基的转录调控所需的将被确定，允许未来的功能研究，以阐明精确的调控机制的ChxR。公共卫生关系：拟议的研究将有助于我们了解如何以及什么控制医学上重要的细菌衣原体的发展和疾病。此外，如本研究中的反应调节剂广泛存在于细菌中，而在哺乳动物中不存在，因此是开发新抗菌剂的有吸引力的目标。