AN INTEGRATED APPROACH TO PREDICTING ONCOGENIC MUTATIONS IN NOVEL BREAST CANCER

预测新型乳腺癌致癌突变的综合方法

• 批准号: 8364289
• 负责人: Rachel Karchin
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364289
• 关键词: 1-Phosphatidylinositol 3-Kinase; Automobile Driving; Biomedical Research; Boxing; Breast; Catalytic Domain; Development; Funding; Grant; High Performance Computing; Human; In Vitro; Location; Malignant Neoplasms; Mutate; Mutation; National Center for Research Resources; Oncogenic; PIK3CA gene; Phosphotransferases; Principal Investigator; Protein Isoforms; Proteins; Reporting; Research; Research Infrastructure; Resources; Solvents; Somatic Mutation; Source; Structure; System; United States National Institutes of Health; Water; Work; cost; gain of function; in vivo; insight; malignant breast neoplasm; molecular dynamics; novel; simulation; tumor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Somatic mutations in PIK3CA (phosphatidylinositol-3 kinase, catalytic subunit, alpha isoform) are reported in breast and other human cancers to concentrate at hotspots within its kinase and helical domains. Most of these mutations cause kinase gain of function in vitro and are associated with oncogenicity in vivo. However, little is known about the mechanisms driving tumor development. Recent work has suggested the existence of three distinct mechanisms that produce an oncogenic PIK3CA protein depending on the structural location of the mutated residue. We propose that we can gain insight on the structural impact of oncogenic somatic mutations in PIK3CA and the existence of this multiple mechanism hypothesis by exploring conformational changes that result from these mutations using extensive molecular dynamics simulations. Our simulations will involve the PIK3CA crystal structure that contains both the PIK3CA catalytic and regulatory subunits, solvated in an explicit water solvent box resulting in the total system size of ~305063 atoms.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 据报道，PIK3CA(磷脂酰肌醇-3激酶，催化亚基，α亚型)的体细胞突变在乳腺癌和其他人类癌症中集中在其激酶和螺旋结构域的热点。这些突变中的大多数在体外都会导致激酶功能的增强，并与体内的致癌作用有关。然而，人们对驱动肿瘤发展的机制知之甚少。最近的工作表明，根据突变残基的结构位置，存在三种不同的机制来产生致癌的PIK3CA蛋白。我们认为，通过使用广泛的分子动力学模拟来探索这些突变导致的构象变化，我们可以深入了解PIK3CA致癌体细胞突变的结构影响以及这一多机制假说的存在。我们的模拟将涉及包含PIK3CA催化和调节亚基的PIK3CA晶体结构，在显式水溶剂箱中溶剂化，导致总体系尺寸为~305063个原子。