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: 7370466
• 负责人: YI TANG
• 金额: $ 0.19万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370466
• 关键词: CRYSTAL; STRUCTURE; POLYKETIDE; SYNTHASES; BASED

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.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。聚酮类化合物是一类结构多样的天然产物，具有重要的药理活性，如抗癌、抗生素、抗病毒和免疫抑制特性。(世界上最畅销的药物中有20%是聚酮类药物。)聚酮合成酶(PKSS)是聚酮生物合成的催化剂，它通过酰基-辅酶A硫酯之间的重复缩合来组装聚酮的碳骨架，因此聚酮结构的多样性部分源于不同的起始单元或延伸单元的加入，起始单元和扩展单元的选择是由PKS中的酰基转移酶(AT)完成的。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。到目前为止，只有放线菌素聚酮合成酶中的丙二酸特异性AT(MAT)被结晶，而模块化PKS中不同底物专一性的AT结构域的结构还没有解决，对其底物专一性的结构基础知之甚少。SSRL的束流时间将被用来解决模块化PKS中MAT突变体、衬底-MAT共晶和AT结构域的晶体结构，旨在基于结构的新型聚酮设计。我们在SSRL利用光束时间的第二个重大发现是R1128聚酮合成酶中功能未知的酶zhC的晶体结构。该序列与MAT序列同源，被认为是R1128聚酮合成酶中的酰基转移酶，但其实际功能尚不清楚。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，我们将确定与免疫原性α2肽结合的人类白细胞抗原-DQ2的晶体结构，这是导致乳糜泻的原因。