PROTEIN-PROTEIN AND PROTEIN-NUCLEOTIDE INTERACTIONS IN MICROTUBULE ASSEMBLY

微管组装中的蛋白质-蛋白质和蛋白质-核苷酸相互作用

• 批准号: 3838121
• 负责人: E HAMEL
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3838121
• 关键词: antimitotics; antineoplastics; beryllium; binding proteins; chemical synthesis; divalent cations; drug design /synthesis /production; guanine nucleotides; guanosine triphosphate; hydrolysis; intermolecular interaction; magnesium; microtubule associated protein; microtubules; nucleotide analog; polymerization; precipitation; protein structure; tubulin

The rational development of new antineoplastic agents directed against tubulin, a protein critical for cell division, requires greater understanding of the interaction between the polypeptide subunits of tubulin, its two tightly bound guanine nucleotides, and microtubule-associated proteins (MAPs). The effects of nucleotides on the stability of microtubules continued to be examined, as were conditions to optimize the separation of alpha-tubulin and beta-tubulin on a preparative scale. The purification of a microtubule-associated protein which causes the formation of microtubule bundles continued to progress, and a project to introduce potentially antimitotic nucleotide analogs into cells continued. Roles of divalent cations in nucleotide binding to tubulin, in tubulin polymerization and in polymer stability were examined. In particular, major differences in effects of Mg2+ and Be2+ on tubulin polymerization, tubulin precipitation, polymer stability, and nucleotide binding and hydrolysis were evaluated in detail. Additional cations were also evaluated for effects on these reactions. Studies were initiated to examine in greater detail the role of Mg2+ in the binding of GTP at the exchangeable site and in microtubule assembly. We have succeeded in synthesizing 2',3'-dideoxyguanosine 5'-[alpha, beta-methylene]-triphosphate, and we are evaluating its effects on microtubule assembly.

针对的新抗塑料剂的合理发展 微管蛋白是一种至关重要的细胞分裂的蛋白质，需要更大 了解多肽亚基之间的相互作用 微管蛋白，其两个紧密结合的鸟嘌呤核苷酸和 微管相关蛋白（地图）。 核苷酸对 微管的稳定性继续检查 优化α-微管蛋白和β-微管蛋白分离的条件 在准备量表上。 微管相关的纯化 导致微管束的形成的蛋白质继续 进度和一个引入潜在抗魔法核苷酸的项目 类似于细胞的类似物继续。 二价阳离子在核苷酸中的作用 在小管蛋白聚合和聚合物稳定性中与微管蛋白结合 被检查。 特别是，MG2+和 BE2+在微管蛋白聚合，微管蛋白沉淀，聚合物稳定性，聚合物稳定性， 详细评估了核苷酸结合和水解。 还评估了其他阳离子对这些反应的影响。 开始研究MG2+在 GTP在可交换位点和微管组件中的结合。 我们成功地合成了2'，3'-二维鸟苷5' - [alpha， β-甲基二磷酸酯，我们正在评估其对其对 微管组件。