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.

该副本是利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，这不一定是调查员的机构。 聚酮化合物是具有具有药理学重要活性的结构多样性的天然产品，例如抗癌，抗生素，抗病毒和免疫抑制性能。 （世界上有20％的高销量销售药物是聚酮化合物。）聚酮化合物的生物合成是由多酮合成酶（PKSS）催化的，这些合成酶（PKSS）通过反复的凝结物来组装聚酮化合物的碳骨架，这是通过乙基含量的抗多孔和多样性在多吉碱结构中的多样性而定，因此在多孔中的多样性，或者在多个群体中取得了不同的选择，或者融合了多个焦点，或者在多个群体中均取代，或者在多孔中的多样化，或者组合在一起，或者融合了零星的凝聚力，而不是偶然的凝结物，而又有零星的凝聚力，而不是偶然性的凝聚力，那么单位是通过PKS中的酰基转移酶（AT）进行的。确定AT的晶体结构将通过蛋白质工程或底物工程来极大地促进新型聚酮化合物的产生。到目前为止，仅在肌动蛋白聚酮化合酶合酶中（MAT）的丙二酰词特异性已经结晶了，而模块化PKS中具有不同底物特异性的AT结构均未得到解决，并且对其底物特异性的结构基础知之甚少。 SSRL处的光束时间将用于求解MAT突变体，底物 - 矩阵共晶和模块化PK中的域的晶体结构，旨在探索基于结构性的新型Polyketide设计。我们利用SSRL的光束时间的第二个主要发现是R1128 Polyketide合酶中功能未知酶的晶体结构。 Zhuc的序列与MAT同源。有人认为它是R1128聚酮化合酶中的酰基转移酶，但其实际功能仍然不清楚。第三，我们目前正在说服完整的多层DEB蛋白的结构确定。第四，我们将确定与腹腔疾病负责的免疫原性α2-肽复合的HLA-DQ2的晶体结构。