PROBING ALLOSTERY IN METHYL-LYSINE READER DOMAINS

探索甲基赖氨酸阅读器结构域中的变构

• 批准号: 10558469
• 负责人: Stephen Vernon Frye
• 金额: $ 42.58万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558469
• 关键词: Address; Area; Binding; Biological Assay; Biology; Biophysics; Catalytic Domain; Cell Lineage; Cells; Chemicals; Chromatin; Complement; Complex; DNA; Disease; Eukaryotic Cell; Family; Future; Gene Expression; Genome; Histones; Intellectual Property; Intervention; Knowledge; Lysine; Molecular; Nucleotides; Outcome; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Post-Translational Protein Processing; Productivity; Proteins; RNA; Reader; Regulation; Research; Resources; Risk; Role; Scientific Advances and Accomplishments; Talents; Therapeutic; Therapeutic Intervention; Time; Training; Validation; academic program; assay development; drug discovery; experience; flexibility; frontier; histone modification; in vitro Assay; in vivo; interest; pharmacologic; small molecule; temporal measurement; transcription factor

PROBING ALLOSTERY IN METHYL-LYSINE READER DOMAINS Abstract: Chromatin is the complex of histone proteins, RNA, and DNA that dynamically packages the genome within each eukaryotic cell. While cell lineage specific transcription factors clearly play a dominant role in the control of gene expression, the regulation of chromatin accessibility via post-translational modifications (PTM) of histones is of great current interest as the opportunities for pharmacological intervention in the action of the associated proteins are significantly better than in the direct perturbation of transcription factors by small molecules. The molecular details of chromatin regulation are just beginning to be understood and chemical biology is poised to play a central role in advancing scientific knowledge and assessing therapeutic opportunities in this field. Specifically, cell penetrant, high-quality chemical probes that modulate the regulation of chromatin state are of great significance. The advantages of a small molecule driven approach to exploring chromatin biology are numerous: temporal resolution; mechanistic flexibility; ease of delivery in cells and potentially, in vivo; and significantly, a chemical probe may provide an immediate transition to a drug discovery effort, possibly cutting years off the time between target selection and therapeutic intervention. This impact of a chemical probe results from simultaneously addressing target ‘validation risk’ (the likelihood that pharmacologic modulation of the target will have a favorable outcome in a disease) and ‘technical risk’ (the likelihood that a tolerable molecule that modulates the target can be discovered). While probes often lack some features required in drugs, their discovery diminishes many target validation and technical risks and creates a cascade of assays, structural and mechanistic information that is enabling to subsequent efforts focused on drugs. While high-quality probes are challenging to develop, they are achievable within the resources available to academic programs, and their creation is a fantastic training experience. To maximize the impact of our probes, we intend to continue our approach of sharing them without creation of intellectual property. We have pioneered a target-class probe discovery strategy within the large family of methyl-lysine (Kme) readers. We have been productive in this area and built momentum for future studies focused on the allosteric interactions between Kme reader domains, nucleotide binding domains, and the catalytic domains that regulate chromatin function. During this effort, we have established a network of talented collaborators that complement our strengths in chemical biology, medicinal chemistry, in vitro assay development, and biophysics; with strengths in molecular, structural and chromatin biology. Allosteric interactions in chromatin regulatory complexes are critically important phenomena that create unique opportunities for pharmacologic intervention. We will focus our future endeavors on this exciting frontier in the Kme reader family.

甲基赖氨酸阅读区的合金化研究 摘要：染色质是组蛋白、RNA和DNA的复合体， 每个真核细胞内的基因组。虽然细胞谱系特异性转录因子明显起主导作用， 在基因表达的控制中，通过翻译后修饰调节染色质可及性 (PTM)组蛋白的作用是当前的一大兴趣，因为药物干预的机会， 的相关蛋白质显着优于在直接扰动转录因子的小 分子。染色质调控的分子细节才刚刚开始被理解和化学 生物学准备在推进科学知识和评估治疗方面发挥核心作用。 这个领域的机会。具体来说，细胞渗透剂，高品质的化学探针，调节调节 染色质状态的变化具有重要意义。小分子驱动的探索方法的优势 染色质生物学是众多的：时间分辨率;机械灵活性;易于在细胞中递送， 潜在地，在体内;并且重要的是，化学探针可以提供药物发现的立即过渡 这可能会缩短目标选择和治疗干预之间的时间。A的影响 同时解决目标“验证风险”（ 靶点的药理学调节将在疾病中具有有利的结果）和“技术风险”（ 可以发现调节靶标的可耐受分子的可能性）。虽然探测器通常缺乏一些 药物所需的功能，它们的发现减少了许多目标验证和技术风险，并创造了一个 级联的分析，结构和机制信息，使后续的努力集中在 毒品虽然开发高质量的探头具有挑战性，但在现有资源范围内是可以实现的 到学术课程，他们的创造是一个梦幻般的培训经验。为了最大限度地发挥我们 探测器，我们打算继续我们的做法，分享他们没有创造知识产权。 我们在甲基赖氨酸大家族中开创了一种靶类探针发现策略 (Kme)读者我们在这方面一直卓有成效，并为未来的研究建立了动力，重点是 Kme阅读器结构域、核苷酸结合结构域和催化结构域之间的变构相互作用 调节染色质功能的基因。在此过程中，我们建立了一个由才华横溢的合作者组成的网络， 补充我们在化学生物学、药物化学、体外分析开发方面的优势， 生物物理学;在分子，结构和染色质生物学的优势。染色质中的变构相互作用 调节复合物是非常重要的现象，为药理学研究创造了独特的机会。 干预我们将把我们未来的努力集中在Kme阅读器家族的这一令人兴奋的前沿领域。