X-RAY STUDIES ON NUCLEIC ACID CONSTITUENTS

核酸成分的 X 射线研究

• 批准号: 2172313
• 负责人: MUTTAIYA SUNDARALINGAM
• 金额: $ 21.11万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2172313
• 关键词: RAY; STUDIES; NUCLEIC; ACID; CONSTITUENTS

The focus of this proposal is to elucidate the three dimensional x-ray structures of synthetic A-DNA, chimeric DNA-RNA, 2:1 side-by-side drug B-DNA and chimeric.drug complexes. These investigations will determine novel nucleic acid structures and provide insights into the details of the atomic structures of base pairing schemes, base multiples, backbone kinks, bends and other distortions. Studies will be continued on alternating A-DNAs to explore alternating conformational characteristics and polymorphous/isomorphous crystals to obtain more information that will aid in separating crystal packing effects from base sequence effects. Chimeric decamers with 1-9 runs of ribose residues, will be investigated and the deoxy and ribose segments will be examined for conformational differences. 2:1 DNA-complexes with minor groove binding drugs will be extended to alternating AT containing sequences to better understand the structure of poly(dA-dT). Similar drug binding studies with chimers are underway. Whenever possible very high resolution structures will be determined with thermal anisotropic refinement to more precisely define the conformational features, motions and hydration of DNA. The long range plans are to study other unusual nucleic acid structures and their interactions. The oligomers for the studies will be synthesized in our laboratory using chemical methods and crystallized using the hanging drop- technique. X-ray data will be collected on our area detector and R-axis imaging plate system. The structures will be solved by molecular replacement or by isomorphous/anomalous heavy atom methods and fitted into the electron density using computer graphics. The XPLOR/NUCLSQ programs will be used for refinement. The results of our studies will provide details, at the molecular level, to better understand gene regulation and rational drug design, which will have an impact on human health.

该提案的重点是阐明三个维度 合成 A-DNA、嵌合 DNA-RNA 的 X 射线结构，2:1 并排 药物 B-DNA 和嵌合药物复合物。这些调查将 确定新的核酸结构并提供对 碱基配对方案、碱基倍数的原子结构的详细信息， 脊柱扭结、弯曲和其他扭曲。将继续研究 交替 A-DNA 探索交替构象特征 和多晶/同晶晶体以获得更多信息 有助于将晶体堆积效应与碱基序列效应分开。 将研究具有 1-9 次核糖残基的嵌合十聚体 并且将检查脱氧和核糖片段的构象 差异。具有小沟结合药物的 2:1 DNA 复合物将 扩展到包含交替 AT 的序列，以更好地理解 聚（dA-dT）的结构。 类似的嵌合体药物结合研究有 进行。只要有可能，就会有非常高分辨率的结构 通过热各向异性细化确定，以更精确地定义 DNA 的构象特征、运动和水合作用。远距离 计划是研究其他不寻常的核酸结构及其 互动。用于研究的低聚物将在我们的合成 实验室使用化学方法并使用悬滴结晶 技术。 X 射线数据将在我们的区域探测器和 R 轴上收集 成像板系统。结构将通过分子解决 替换或通过同晶/异常重原子方法并拟合成 使用计算机图形学计算电子密度。 XPLOR/NUCLSQ 计划 将用于细化。我们的研究结果将提供 在分子水平上详细了解基因调控和 合理的药物设计，将对人类健康产生影响。