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组织素脱甲基酶JMJD2A的晶体结构揭示了基质特异性的基础
Stanley S Ng1, Kathryn L Kavanagh, Michael A McDonough
1Structural Genomics Consortium, Botnar Research Center, University of Oxford, Oxford OX3 7LD, UK.
Nature
|June 26, 2007
概括
研究人员发现了JMJD2A酶如何区分 histone 蛋白的不同甲基化状态. 这一发现是理解表观遗传调节和开发新药的关键.
科学领域:
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 染色体生物学 染色体生物学
- 分子生物学分子生物学
背景情况:
- 包括甲基化在内的翻译后的基因组修饰对于表观遗传调节至关重要.
- 基脱甲基酶去除甲基组,挑战了甲基化作为永久表观遗传标记的观点.
- 了解脱甲基酶的选择性对于破译它们在生物过程中的作用至关重要.
研究的目的:
- 阐明人类JMJD2A (含有2A的jumonji域) 实现对特定基因素甲基化状态 (H3K9me3/me2和H3K36me3/me2) 的选择性.
- 了解JMJD2A如何区分甲基化状态并识别特定序列,特别是H3K9.
主要方法:
- 对JMJD2A抑制剂复合物的X射线晶体学结合于各种甲基化素H3 (H3K9me3/me2/me1和H3K36me3).
- 在JMJD2A活性部位内对基质结合的结构分析.
主要成果:
- 结构洞察力揭示了一个 lysyl 结合口袋,其中基板采用明显的曲形状.
- 结合部位在基质的识别和结合中起作用.
- 一个拟议的机制解释了基甲基化状态的选择性,该选择性基于相对于铁中间体的甲基基组定向.
结论:
- 对于不同的甲基化状态和序列,JMJD2A表现出不同的识别机制.
- 这些发现为开发药物发现的化学工具提供了基础.
- 这项研究有助于更好地理解可逆组织素甲基化及其在染色体生物学中的作用.
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...
02:25Spreading of Chromatin Modifications
The histone proteins in the nucleosomes are post-translationally modified (PTM) to increase or decrease access to DNA. The commonly observed PTMs are methylation, acetylation, phosphorylation, and ubiquitination of lysine amino acids in the histone H3 tail region. These histone modifications have specific meaning for the cell. Hence, they are called "histone code". The protein complex involved in histone modification is termed as "reader-writer" complex.
Writers
The writer is an enzyme that can...
Writers
The writer is an enzyme that can...