Molecular principles of translation termination

翻译终止的分子原理

基本信息

批准号：
8818358
负责人：
Andrei Korostelev
金额：
$ 32.24万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2015-01-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8818358
关键词：
Accounting Address Amino Acyl Transfer RNA Anti-Bacterial Agents Antibiotics Bacteria Biochemical Biological Assay Catalytic Domain Cell physiology Cells Charcot-Marie-Tooth Disease Codon Nucleotides Collaborations Complement Complex Consult Coupled Data Development Disease Drug effect disorder Duchenne muscular dystrophy Elongation Factor Ensure Eubacterium Eukaryota Event Foundations Frequencies Frontotemporal Dementia Glare Goals Guanosine Triphosphate Phosphohydrolases Health Hereditary Disease Human Hydrolysis Imagery Kinetics Lead Length Letters Link Methods Molecular Molecular Conformation Molecular Machines Nonsense Codon Nonsense-Mediated Decay Normal Cell Open Reading Frames Organism Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Play Protein Biosynthesis Proteins Qualifying Regulation Research Resolution Ribosomes Role Route Saccharomyces cerevisiae Sense Codon Specificity Structure System Terminator Codon Testing Therapeutic Translations Validation Work chemical synthesis design drug development high throughput screening insight molecular dynamics nervous system disorder novel novel therapeutics peptidyl-tRNA polypeptide premature prevent release factor screening single-molecule FRET small molecule therapeutic development tool

项目摘要

DESCRIPTION (provided by applicant): Translation in all organisms is performed by the ribosome, one of the most ancient and universally conserved molecular machines. Termination is the last step of protein synthesis, which ensures that expressed proteins have lengths strictly defined by the corresponding open reading frames. This critical step should be accurate and efficient to prevent accumulation of truncated or overly long polypeptide products that can be toxic to cell. Whereas most steps of translation and corresponding extraribosomal factors (e.g. elongation factors) are highly conserved between bacteria and eukaryotes, the termination of translation is not. In human, premature termination is associated with a large number of genetic diseases. These unique features place termination as a promising target for development of drugs. A detailed understanding of bacterial translation termination may provide us with tools to develop antibacterial drugs. Elucidation of the molecular mechanism of eukaryotic termination is necessary to design or search for therapeutics to target human neurological diseases linked to premature termination. In this proposal, we will gain insights into molecular mechanisms of termination in both bacteria and eukaryotes. In Aim 1, we will determine crystal structures of intermediate conformational steps of termination on the bacterial 70S ribosome. This will provide insights into how a remarkable accuracy is achieved by bacterial release factors RF1 and RF2. In Aim 2, we will study termination on the eukaryotic 80S ribosome. Here, essential class I release factor eRF1 and class II release factor eRF3 are involved, which are structurally distinct from their bacterial counterparts. In Aim 3, we will explore new therapeutic routes against diseases caused by premature termination. The long-term goals of our studies are to gain detailed mechanistic insights into key cellular processes involving translation, and to contribute to therapeutics development.

描述（由申请人提供）：所有生物体中的翻译都是由核糖体进行的，核糖体是最古老，保守的分子机器之一。终止是蛋白质合成的最后一步，它确保表达蛋白质的长度严格由相应的开放式阅读框定义。这一关键步骤应准确而有效，以防止可能对细胞有毒的截短或过长的多肽产物积累。虽然大多数翻译和相应的外粒体因子（例如伸长因子）在细菌和真核生物之间高度保守，但翻译的终止却不是。在人类中，过早终止与大量遗传疾病有关。这些独特的特征将终止作为毒品开发的有希望的目标。对细菌翻译终止的详细了解可能为我们提供了开发抗菌药物的工具。为了设计或寻找针对与早产相关的人类神经系统疾病的治疗剂，必须阐明真核终止的分子机制。在此提案中，我们将深入了解细菌和真核生物中终止的分子机制。在AIM 1中，我们将确定细菌70S核糖体上终止中间构象步骤的晶体结构。这将提供有关细菌释放因子RF1和RF2如何实现明显准确性的见解。在AIM 2中，我们将研究真核80年代核糖体的终止。在这里，I -Class I类释放因子ERF1和II类释放因子ERF3在结构上与细菌对应物不同。在AIM 3中，我们将探索针对由过早终止引起的疾病的新治疗途径。我们研究的长期目标是获得有关涉及翻译的关键细胞过程的详细机械见解，并为治疗学的开发做出贡献。