Molecular recognition in post-transcriptional regulation 2

转录后调控中的分子识别2

• 批准号: MC_PC_13051
• 负责人: Andres Ramos
• 金额: $ 114.04万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_PC_13051
• 关键词: Molecular; recognition; post; transcriptional; regulation

The functioning of the human body and of complex organisms in general requires different proteins to be produced in different types of cells. This cell-type-specific protein production is achieved by precisely regulating the translation of the genetic code into proteins. The two steps in this process of translation are, first, the translation of the DNA-encoded information into RNA and, then, the translation of the RNA code into a protein molecule. Both processes are regulated by biological machines, which are composed of proteins and, in some cases, RNA molecules. We focus on the regulation of the RNA-to-protein step (or post-transcriptional regulation) and investigate how the protein RNA machines assemble in a solution environment and regulate gene expression. Our structural studies complement other techniques such as X-ray crystallography, which can be used to study molecules in a static crystalline state. Analysing the structures of the molecules that govern regulation of protein synthesis has a direct medical relevance, as this process lies at the basis of common genetic diseases, cancer and viral infections. We work on an important regulatory mechanism, called ARE mediated mRNA decay (AMD), that increase the synthesis of specific proteins in inflammation and healing processes. This mechanism, if permanently switched on, can lead to inflammatory arthritis and cancer. We want to understand how the switch works at the molecular level and design specific therapies to switch in off when required.||Using a similar technical approach we are also investigating a key regulatory protein from herpes virus. This project wants to facilitate the design of anti-herpes drugs to treat people infected with this virus, which forms a major threat to immunodepressed patients, increases the risk of organ transplantation and chemotherapy and reduces the life expectancy of AIDS sufferers. Molecular insight into the interaction of ICP27 with its functional binding partners needs to be obtained if we are, for example, to design or optimise compounds to lock protein and RNA in a non-functional conformation or to (de)stabilise protein RNA complexes.

人体和复杂生物体的功能通常需要不同类型的细胞产生不同的蛋白质。这种细胞类型特异性蛋白质的产生是通过精确调节遗传密码翻译成蛋白质来实现的。这个翻译过程有两个步骤，首先是将DNA编码的信息翻译成RNA，然后是将RNA编码翻译成蛋白质分子。这两个过程都受到生物机器的调节，生物机器由蛋白质组成，在某些情况下，RNA分子。我们专注于RNA到蛋白质的步骤（或转录后调节）的调节，并研究蛋白质RNA机器如何在溶液环境中组装并调节基因表达。我们的结构研究补充了其他技术，如X射线晶体学，可用于研究静态晶体状态下的分子。分析控制蛋白质合成调节的分子结构具有直接的医学意义，因为这一过程是常见遗传疾病、癌症和病毒感染的基础。我们研究一种重要的调节机制，称为ARE介导的mRNA衰变（AMD），它增加了炎症和愈合过程中特定蛋白质的合成。这种机制，如果永久开启，可能导致炎症性关节炎和癌症。我们想了解这个开关在分子水平上是如何工作的，并设计出特定的治疗方法，以便在需要时关闭开关。||使用类似的技术方法，我们也在研究疱疹病毒的关键调节蛋白。该项目希望促进抗疱疹药物的设计，以治疗感染这种病毒的人，这种病毒对免疫抑制患者构成重大威胁，增加器官移植和化疗的风险，并减少艾滋病患者的预期寿命。ICP27与其功能性结合伙伴的相互作用的分子洞察力需要获得，例如，如果我们要设计或优化化合物，以锁定蛋白质和RNA在非功能性构象或（去）稳定蛋白质RNA复合物。

项目成果

Protein-RNA specificity by high-throughput principal component analysis of NMR spectra.

• DOI: 10.1093/nar/gku1372
• 发表时间: 2015-03-31
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Collins KM;Oregioni A;Robertson LE;Kelly G;Ramos A
• 通讯作者: Ramos A

The distinct RNA-interaction modes of a small ZnF domain underlay TUT4(7) diverse action in miRNA regulation

小 ZnF 结构域的独特 RNA 相互作用模式是 TUT4(7) 在 miRNA 调节中多种作用的基础

• DOI: 10.6084/m9.figshare.16912173
• 发表时间: 2021
• 作者: Chaves-Arquero B

Structural basis for Fullerene geometry in a human endogenous retrovirus capsid

人内源性逆转录病毒衣壳中富勒烯几何结构的结构基础

• DOI: 10.25418/crick.11695149
• 发表时间: 2020
• 作者: Acton O

Terminal loop-mediated regulation of miRNA biogenesis: selectivity and mechanisms.

• DOI: 10.1042/bst20130058
• 发表时间: 2013-08
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Castilla-Llorente V;Nicastro G;Ramos A
• 通讯作者: Ramos A

Structure of a Spumaretrovirus Gag Central Domain Reveals an Ancient Retroviral Capsid.

• DOI: 10.1371/journal.ppat.1005981
• 发表时间: 2016-11
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Ball NJ;Nicastro G;Dutta M;Pollard DJ;Goldstone DC;Sanz-Ramos M;Ramos A;Müllers E;Stirnnagel K;Stanke N;Lindemann D;Stoye JP;Taylor WR;Rosenthal PB;Taylor IA
• 通讯作者: Taylor IA