对人类原体家族的基质子识别和大规模结构分析
Panagis Filippakopoulos1, Sarah Picaud, Maria Mangos
1Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7LD, UK. panagis.filippakopoulos@sgc.ox.ac.uk
Cell
|April 3, 2012
概括
基体 (BRDs) 识别表观遗传标记. 这项研究揭示了BRD家族中保存和独特的结构特征,揭示了新的基质以及修改如何影响药物设计的结合.
科学领域:
- 结构生物学是结构生物学.
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 蛋白质与蛋白质之间的相互作用
背景情况:
- 基基因 (BRD) 是关键的表观遗传阅读器,它们与乙化氨酸残留物结合.
- 人类基因组包含61个BRD,根据结构和序列相似性被分为八个家族.
- 了解BRD结构和功能对于表观遗传学研究和治疗开发至关重要.
研究的目的:
- 展示来自所有八个家族的29个多样化的体 (BRD) 的高分辨率晶体结构.
- 分析控制乙化依赖基质识别的保存和家族特异性结构特征.
- 确定新的BRD基质,并了解转化后修改在BRD结合中的作用.
主要方法:
- 进行X射线晶体学以确定29个高分辨率的BRD结构.
- 跨家族结构分析以确定保存和独特的特征.
- 对30多个BRD进行系统选,对其进行基因组-基因组测试.
主要成果:
- 对所有八个BRD家族的详细结构洞察力,突出了特定基质识别的特征.
- 识别新的BRD基质,并证明侧向乙化和酸化如何影响结合.
- 阐明BRD4识别二甲基化的结构机制.
结论:
- 提出的结构为了解BRD-表观遗传标记相互作用提供了全面的资源.
- BRD识别受到翻译后修改组合的影响,而不仅仅是单个乙化事件.
- 这些发现为基于结构的药物设计奠定了基础,针对特定的BRD抑制剂.
相关概念视频
02:32Histone Modification
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
02:32Histone Modification
The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
01:12The Nucleosome Core Particle
Nucleosomes are the DNA-histone complex, where the DNA strand is wound around the histone core. The histone core is an octamer containing two copies of H2A, H2B, H3, and H4 histone proteins.
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their primary aim is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. On the other hand, they must allow polymerase enzymes to access histone-bound DNA during...
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their primary aim is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. On the other hand, they must allow polymerase enzymes to access histone-bound DNA during...
02:10The Nucleosome Core Particle
Nucleosomes are the DNA-histone complex, where the DNA strand is wound around the histone core. The histone core is an octamer containing two copies of H2A, H2B, H3, and H4 histone proteins.
The paradox
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their main responsibility is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. While on the other hand, they must allow polymerase enzymes to access DNA...
The paradox
Nucleosomes, paradoxically, perform two opposite functions simultaneously. On the one hand, their main responsibility is to protect the delicate DNA strands from physical damage and help achieve a higher compaction ratio. While on the other hand, they must allow polymerase enzymes to access DNA...
02:30Histone Variants at the Centromere
Histone variants are the histone proteins with structural and sequence variations. These variants may be regarded as “mutant” forms that replace their canonical histone counterparts in the nucleosomes. Specific post-translational modifications on the histone variants enable further chromatin complexity and regulate tissue-specific gene expression. The most common histone variants are from histone H2A, H2B, and linker histone H1 families. However, several variants of histone H3 variants are also...
01:19The Nucleosome
Human DNA is almost two meters long. However, it is compressed inside a tiny nucleus measuring only a few microns in diameter. To make this degree of compaction possible, DNA is organized into several sequential levels so that it can fit into such a tiny space. The most compact form of DNA is a chromosome that can be seen under a microscope in a dividing cell.
In a chromosome, DNA is wound twice around a protein complex called a histone octamer core, which consists of 8 histone proteins. This...
In a chromosome, DNA is wound twice around a protein complex called a histone octamer core, which consists of 8 histone proteins. This...