CRYSTAL STRUCTURES OF POLYKETIDE MEGA-SYNTHASE

聚酮大合成酶的晶体结构

• 批准号: 8170175
• 负责人: Shiou-Chuan Tsai
• 金额: $ 0.21万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170175
• 关键词: Antibiotics; Chemicals; Cholesterol; Complex; Computer Retrieval of Information on Scientific Projects Database; Cyclization; Doxorubicin; Erythromycin; Funding; Grant; HIV; Housing; Institution; Investigation; Lovastatin; Modification; Molecular; Molecular Structure; Multienzyme Complexes; Outcome; Pharmaceutical Preparations; Property; Public Health; Reaction; Research; Research Personnel; Resources; Running; Source; Specificity; Structure; Tetracyclines; United States National Institutes of Health; Variant; base; mutant; polyketide synthase; 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. Polyketides include many important drugs with cholesterol-lowering (such as lovastatin), anticancer (such as doxorubicin and bleomysin) and antibiotic activities (such as tetracycline and erythromycin) with potential HIV applications. Polyketide synthase (PKS) is a multi-domain enzyme complex that produces a huge variety of polyketides via a controlled variation of building blocks and modification reactions, including chain reduction and cyclization. There is a critical gap in the structure and molecular basis of PKS activity. To solve the PKS complex structures, we have crystallized several PKS complexes that diffract to 1.7 ? 2.8 ¿. Because of the size of these complexes, we could not solve them by molecular replacement using single-domain structures. We have already crystallized the PKS complexes as Se, Au and Pt derivatives that diffract in-house to 2.2 ? 4.0 ¿. Therefore, beamtime at SSRL will have a great impact by helping us bring this exciting project to the finish line. As an outcome of the proposed investigations, we expect to determine all three multi-domain complex structures and determine the importance of protein-protein interaction on the polyketide cyclization/termination specificity. The polyketide ring is vital for the antibiotic and anticancer properties of polyketides. The research proposed in this application is significant, because its outcome allows us to elucidate how polyketides are specifically cyclized and terminated at a molecular level that has not been visualized before. In the long run, the result from this proposal will have a significant positive impact on the public health by providing medically useful chemicals via structure-directed mutants of PKS.

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。 聚酮化合物包括许多含有胆固醇的重要药物（例如洛伐他汀），抗癌（例如阿霉素和白血病素）以及具有潜在的HIV应用的抗生素活性（例如四环素和红霉素）。聚酮化合物合酶（PKS）是一种多域酶复合物，通过构建块和修饰反应的控制变化（包括链还原和环化），可通过受控的变化产生各种聚酮化合物。 PKS活性的结构和分子基础存在临界差距。为了解决PKS复合结构，我们已经结晶了几种衍射为1.7的PKS络合物？ 2.8。由于这些复合物的大小，我们无法使用单域结构通过分子替换来解决它们。我们已经将PKS络合物结晶为SE，AU和PT衍生物，内部衍射为2.2？ 4.0。因此，SSRL的Beamtime将通过帮助我们将这一激动人心的项目带入终点线，从而产生很大的影响。作为拟议研究的结果，我们期望确定所有三个多域复杂结构，并确定蛋白质 - 蛋白质相互作用对聚酮化合物环化/终止特异性的重要性。聚酮环环对聚酮化合物的抗生素和抗癌特性至关重要。在本应用中提出的研究很重要，因为它的结果使我们能够在以前尚未可视化的分子水平上特异性地循环和终止聚酮化合物。从长远来看，该提案的结果将通过通过PKS结构定向的突变体提供医学上有用的化学物质对公共卫生产生重大积极影响。