Computational & Biochemical Studies of the Malarial Blood Stage Invasion Complex

计算型

基本信息

批准号：
7545695
负责人：
Sondra Maureen Nemetski
金额：
$ 4.36万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7545695
关键词：
Actins Adhesives Affect Aldehyde-Lyases Anemia Antimalarials Binding Biochemical Biochemistry Biological Assay Biology Blood Cell membrane Cell surface Cells Cerebral Malaria Cerebrum Cessation of life Cilia Communicable Diseases Complex Computational Biology Computer Simulation Crystallography Disease Docking Drug resistance Economic Development Enzymes Erythrocytes Family Fever Flagella Fructosediphosphate Aldolase Future Homology Modeling Human Imagery In Vitro Invaded Invasive Knowledge Laboratories Malaria Membrane Methodology Modeling Molecular Models Motor Movement Myosin ATPase Organ Organism Pain Parasites Plasmodium Plasmodium falciparum Protein Family Proteins Protozoa Public Health Publishing Reporting Research Resolution Site-Directed Mutagenesis Sporozoites Staging Structure Tail Techniques Training Universities Washington Work base blood vessel occlusion cell motility computer studies design drug discovery interdisciplinary approach member mortality novel pathogen social success three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): While effective treatments for malaria exist, parasite resistance to these drugs is growing rapidly, and there is a critical need for new mechanisms to combat this disease. Several recent studies indicate that the motile and invasive machinery of the parasite represents a promising new target for drug discovery. In order to facilitate future drug discovery projects targeting the malarial motor and invasion machinery, this proposal aims to use an interdisciplinary approach to elucidate the structural features of a part of this complex expressed in Plasmodium falciparum merozoites - the invasive blood stage of this parasite, andthe causative agent of cerebral malaria and the majority of malarial mortality. Plasmodia, like other apicomplexan protozoa, employ a mechanism of substrate-dependent gliding motility that does not depend on cilia or flagella. Gliding and host cell invasion are crucial parasite functions and increasingly appear to be driven by an actin/myosin motor located beneath the organism's plasma membrane. Myosin generates movement by forcefully displacing actin. In Plasmodium merozoites, this force is transmitted - viatheactin-binding, glycolytic enzyme, aldolase - to MTRAP, a type I trans-membrane molecule bearing adhesive domains capable of interacting with host-cell surfaces. The parasite uses this force to actively invade human red blood cells. This proposal aims to elucidate the structural features of the MTRAP-aldolase interaction in Plasmodium falciparum merozoites via the biochemical characterization of this complex in vitro and the three-dimensional resolution of the MTRAP-aldolase interface in silico. A combination of site-directed mutagenesis, homology modeling, and computational docking will be used to identify and visualize key contacts between the two proteins. The detailed picture of the structural basis for the MTRAP-aldolase interaction thus obtained will serve as the platform for the future rational design of anti-malarial agents. PUBLIC HEALTH RELEVANCE: Malarial disease affects hundreds of millions of people worldwide - afflicting them with anemia, excruciating pain, fever, and in severe cases, cerebral blood vessel occlusion, organ damage, and death. The research proposed here serves as an ideal training opportunity in computational biology and the biochemistry of a global infectious disease, while simultaneously increasing the current knowledge of a key aspect of malarial biology, and facilitating the design of novel, safe, and effective anti-malarial agents.

描述（由申请人提供）：虽然存在有效的疟疾治疗方法，但对这些药物的寄生虫耐药性正在迅速增长，并且对应对这种疾病的新机制迫切需要。最近的几项研究表明，寄生虫的运动和侵入性机制代表了一个有希望的药物发现目标。为了促进针对疟疾运动和入侵机械的未来药物发现项目，该提议旨在使用跨学科的方法来阐明该复合物的一部分的结构特征，该复合物以恶性疟原虫的纯净植物形式表达，这是该寄生虫的侵入性血液阶段 - 念珠菌和念珠菌和多个多元性的念珠菌。与其他Apicomplexan原生动物一样，疟原虫采用了底物依赖性滑行运动的机制，不依赖于纤毛或鞭毛。滑行和宿主细胞的侵袭是至关重要的寄生虫功能，似乎越来越多地由位于生物体质膜下方的肌动蛋白/肌球蛋白电动机驱动。肌球蛋白通过有力取代肌动蛋白而产生运动。在疟原虫中，这种力是通过抑制蛋白结合，糖酵解酶，醛糖酶 - 到MTRAP的，这是I型的I型跨膜分子，具有能够与宿主细胞表面相互作用的I型跨膜分子。寄生虫利用这种力积极入侵人类的红细胞。该建议旨在通过这种复合物体外的生化表征和硅胶中Mtrap-溶解酶界面的三维分辨率来阐明恶性疟原虫植物元素中MTRAP-溶解酶相互作用的结构特征。位置定向的诱变，同源性建模和计算对接的组合将用于识别和可视化两种蛋白质之间的关键接触。因此获得的MTRAP-溶解酶相互作用的结构基础的详细图片将作为抗疟疾剂的未来合理设计的平台。公共卫生相关性：疟疾疾病会影响全球数亿人 - 使他们患有贫血，痛苦，发烧，严重的情况，脑血管阻塞，器官损害和死亡。这里提出的研究是计算生物学和全球传染病的生物化学的理想培训机会，同时同时增加了对疟疾生物学关键方面的当前知识，并促进了新颖，安全，有效的抗癌症的设计。