CRYSTAL STRUCTURE OF POLYKETIDE SYNTHASES: STRUCTURE-BASED DRUG DESIGN ON NOVEL

聚酮合成酶的晶体结构：基于结构的新型药物设计

• 批准号: 7597984
• 负责人: YI TANG
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7597984
• 关键词: Acyl Coenzyme A; Acyltransferase; Anabolism; Antibiotics; Biological Factors; Carbon; Celiac Disease; Class; Complex; Computer Retrieval of Information on Scientific Projects Database; Drug Design; Engineering; Enzymes; Funding; Grant; Immunosuppressive Agents; Institution; Malignant Neoplasms; Peptides; Pharmaceutical Preparations; Physical condensation; Production; Property; Protein Engineering; Proteins; Research; Research Personnel; Resources; Source; Structure; Substrate Specificity; Time; United States National Institutes of Health; Vertebral column; Virus; base; design; immunogenic; mutant; novel; polyketide beta-ketoacylsynthase; polyketide synthase; thioester

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 are a structurally diverse class of natural products that have pharmacologically important activities, such as anti-cancer, antibiotic, anti-virus, and immunosuppressive properties. (20% of the top selling drugs in the world are polyketides.) The biosynthesis of polyketides is catalyzed by polykeitde synthases(PKSs), which assemble the carbon backbones of polyketides through repeated condensations between acyl-CoA thioesters, so the diversity in polyketide structures is in part derived from the incorporation of different starter or extender units, selection of the starter and extender units is carried out by acyltransferase(AT) in PKS. Determination of the crystal structures of AT will greatly facilitate the production of novel polyketides by protein engineering or substrate-engineering. Thus far, only the malonyl-specific AT (MAT) in actinorhodin polyketide synthase has been crystallized, while none of the structures of AT domains with different substrate specificities in modular PKSs have been solved and little is known about the structural basis for their substrate specificities. Beam time at SSRL will be utilized to solve crystal structures of MAT mutants, substrate-MAT cocrystals and AT domains in modular PKS, aiming at structural-based novel polyketide design. Our second major discovery utilizing beam time at SSRL is the crystal structure of a functionally unknown enzyme ZhuC in R1128 polyketide synthase. The sequence of ZhuC is homologous to MAT; it was proposed to be the acyltransferase in R1128 polyketide synthase, but its actual function is still not clear. Third, we are currently persuing structure determination of an intact multidalton DEBS protein. Fourth, we will determine the crystal structure of HLA-DQ2 complexed with the immunogenic alpha2-peptide, that is responsible for celiac disease.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 聚酮化合物是一类结构多样的天然产物，具有重要的药理学活性，例如抗癌、抗生素、抗病毒和免疫抑制特性。 （全球最畅销的药物中有20%是聚酮化合物。）聚酮化合物的生物合成是由聚酮合酶（PKS）催化，通过酰基辅酶A硫酯之间的反复缩合组装聚酮化合物的碳主链，因此聚酮化合物结构具有多样性部分源自不同启动器或扩展单元的合并，启动器和扩展单元的选择是通过以下方式进行的PKS 中的酰基转移酶 (AT)。 AT晶体结构的确定将极大地促进通过蛋白质工程或底物工程生产新型聚酮化合物。迄今为止，仅结晶了放线菌素聚酮化合物合酶中的丙二酰特异性AT（MAT），而模块化PKS中具有不同底物特异性的AT结构域的结构尚未得到解决，并且对其底物特异性的结构基础知之甚少。 。 SSRL 的束流时间将用于解析模块化 PKS 中 MAT 突变体、基质-MAT 共晶和 AT 结构域的晶体结构，旨在基于结构的新型聚酮化合物设计。我们利用 SSRL 束流时间的第二个重大发现是 R1128 聚酮合酶中功能未知的酶 ZhuC 的晶体结构。 ZhuC的序列与MAT同源；被认为是R1128聚酮合酶中的酰基转移酶，但其实际功能仍不清楚。第三，我们目前正在对完整的多道尔顿 DEBS 蛋白进行结构测定。第四，我们将确定与导致乳糜泻的免疫原性 α2 肽复合的 HLA-DQ2 的晶体结构。