THE STRUCTURAL BASIS FOR THE ASSEMBLY AND REGULATION OF THE MLL CORE COMPLEX

MLL 核心复合体组装和调节的结构基础

• 批准号: 8171507
• 负责人: Michael S. Cosgrove
• 金额: $ 3.95万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171507
• 关键词: Acute leukemia; Amino Acids; Antineoplastic Agents; Binding; Binding Sites; Biological; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA Sequence Rearrangement; Data; Development; Diabetes Mellitus; Epigenetic Process; Funding; Goals; Grant; Hematopoiesis; Histone H3; Homeobox Genes; Housing; Human; Institution; Insulin; Investigation; Lysine; MLL gene; Maps; Methylation; Molecular; Mono-S; Myeloid-Lymphoid Leukemia Protein; Oncogenic; Oral; Outcome; Peptides; Proteins; Regulation; Research; Research Personnel; Resolution; Resources; Role; SET Domain; Site; Solutions; Source; Specificity; Structural Protein; Structure; Testing; United States National Institutes of Health; Vitamin B 12; adduct; base; design; histone methyltransferase; leukemia; monomer; outcome forecast; protein complex; protein protein interaction; Acute leukemia; Amino Acids; Antineoplastic Agents; Binding; Binding Sites; Biological; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA Sequence Rearrangement; Data; Development; Diabetes Mellitus; Epigenetic Process; Funding; Goals; Grant; Hematopoiesis; Histone H3; Homeobox Genes; Housing; Human; Institution; Insulin; Investigation; Lysine; MLL gene; Maps; Methylation; Molecular; Mono-S; Myeloid-Lymphoid Leukemia Protein; Oncogenic; Oral; Outcome; Peptides; Proteins; Regulation; Research; Research Personnel; Resolution; Resources; Role; SET Domain; Site; Solutions; Source; Specificity; Structural Protein; Structure; Testing; United States National Institutes of Health; Vitamin B 12; adduct; base; design; histone methyltransferase; leukemia; monomer; outcome forecast; protein complex; protein protein interaction

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Mixed Lineage Leukemia (MLL) protein catalyzes histone H3 lysine 4 (H3K4) methylation, which is an epigenetic mark essential for the regulation of HOX genes in hematopoiesis and development. Translocations that disrupt the MLL gene are present in a unique group of acute leukemias, often predicting a poor prognosis. Other MLL rearrangements and amplifications increase MLL¿¿"s enzymatic activity and are oncogenic. MLL contains an evolutionarily conserved ~130 amino acid SET domain that catalyzes H3K4 methylation. Recent studies indicate that the enzymatic activity of MLL is regulated by a conserved complex of proteins including WDR5, RbBP5, and ASH2L. These proteins form an independent complex that binds to MLL and regulates MLL¿¿"s ability to mono-, di-, or trimethylate H3K4, a phenomenon known as ¿¿¿Product Specificity¿¿". Since different levels of methylation of H3K4 are associated with different transcriptional outcomes, it is imperative to understand the molecular mechanisms by which the product specificity of MLL is regulated. Despite the important biological role of MLL and its involvement in human leukemia, there is currently little information about the protein-structural features that are responsible for the enzymatic activity of MLL. The long-term goal of this research is to fully characterize the histone methyltransferase activity of MLL to facilitate the identification and rational design of new anti-cancer drugs for the treatment of human leukemias. This proposal takes a structure-function approach to investigate the molecular mechanisms of MLL SET domain regulation by protein-protein interactions. We have mapped the site of interaction between MLL and WDR5, and have obtained crystals of WDR5 with a peptide derived from MLL. The initial structure diffracted to 1.72 angstroms, and elucidtaed the peptide binding site. For this investigation, we would like to obtain higher resolution data with a longer peptide to determine if other interactions between MLL and WDR5 are important. For an unrelated project, we have also recently obtained crystals of an insulin-vitamin B12 adduct, which offers a potential oral alternative for insulin treatment for diabetes. While we have not tested them for diffraction yet (we don`t have an in house diffractometer), we have confirmed that the crystals are protein, and that the insulin B12 adduct forms monomers in solution.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 混合谱系白血病（MLL）蛋白催化组蛋白H3赖氨酸4（H3K4）甲基化，这对于调节造血和发育中HOX基因的表观遗传标记必不可少。破坏MLL基因的易位存在于独特的急性白血病中，通常预测预后不佳。其他MLL重排和扩增会增加MLL酶活性，并且具有致癌性。MLL包含一个进化保守的〜130氨基酸集域，可催化H3K4甲基化。最近的研究表明，MLL的酶活性由蛋白质的蛋白质组成，包括wdr5的蛋白质​​，将MLL的酶活性调节。 MLL和调节的能力是单，DI-或三甲基盐H3K4的能力，这是一种被称为“产品特异性”的现象。在人类白血病中，目前几乎没有有关MLL酶促活性的蛋白质结构特征的信息。该建议采用一种结构功能方法来研究通过蛋白质 - 蛋白质相互作用调节MLL集域调节的分子机制。我们已经绘制了MLL和WDR5之间的相互作用位点，并获得了WDR5的晶体，该晶体具有衍生自MLL的肽。初始结构衍射为1.72埃，并阐明了肽结合位点。对于这项研究，我们希望获得具有更长肽的更高分辨率数据，以确定MLL和WDR5之间的其他相互作用是否重要。对于一个无关的项目，我们最近还获得了胰岛素 - 维生素B12加合物的晶体，该晶体为糖尿病的胰岛素治疗提供了潜在的口服替代方法。虽然我们尚未对它们进行衍射（我们没有内部衍射仪）的衍射（我们都没有衍射仪），但我们已经确认晶体是蛋白质，并且胰岛素B12加合物在溶液中形成单体。