CRYSTAL STRUCTURES OF POLYKETIDE SYNTHASES: STRUCTURE-BASED DRUG DESIGN OF 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: 7721852
• 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: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721852
• 关键词: 6 Deoxyerythronolide B Synthase; Accounting; Acyl Carrier Protein; Antibiotics; Architecture; Biological Factors; Carboxylic Acids; Class; Computer Retrieval of Information on Scientific Projects Database; Drug Design; Engineering; Exhibits; Funding; Goals; Grant; Immunosuppressive Agents; Individual; Institution; Libraries; Malignant Neoplasms; Marketing; Modification; Nature; Organic Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Property; Protein Engineering; Protein Fragment; Proteins; Range; Research; Research Personnel; Resources; Source; Structure; System; Type I Polyketide Synthase; United States National Institutes of Health; Virus; analog; base; crosslink; drug discovery; insight; next generation; novel; picromycin; polyketide synthase; protein structure

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 exhibit a diverse range of pharmacologically relevant activities including anti-cancer, antibiotic, anti-virus, and immunosuppressive properties, accounting for $ 30 billion of the worldwide pharmaceutical market in 2005. They are synthesized in nature from a limited repertoire of simple carboxylic acids by multifunctional proteins called polyketide synthases (PKSs). Type I PKSs, the target of the current study have a modular architecture. Determination of crystal structures of PKSs will greatly aid in systematically exploring the architectural features of the system and yield key insights into critical features such as domain boundary and substrate selectivity. This would in turn allow modification of PKSs by protein-engineering or substrate-engineering to produce the next generation of "unnatural" polyketide products. In the recent past we have solved the crystal structure of a 194 kDa homodimeric fragment of the 6-deoxyerythronolide B synthase(6-DEBS), in addition to the crystal structures of two thioesterases from 6-DEBS and picromycin polyketide synthase respectively and the crystal structure of priming ketosynthase (ZhuH) from R1128 polyketide synthase solved earlier utilizing the beamtime at SSRL. Given the importance of the polyketides in synthetic organic chemistry and drug discovery, solving the crystal structures of these proteins is only the beginning of structure-based drug design utilizing PKSs with the ultimate goal of accessing a variety of synthetic analogs which would serve as a library of macrocycle drug leads. In continuation with our studies on the structure of these proteins, beamtime at SSRL will be utilized to solve the crystal structures of a ketosynthase (KS)-acyl carrier protein (ACP) protein fragment which will be obtained via irreversible covalent cross-linking of the 2 individual domains from module 3 DEBS.

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。 聚酮化合物是一种结构上多样化的天然产品，表现出各种各样的药理学相关活动，包括抗癌，抗生素，抗生素，抗病毒和免疫抑制性能，在2005年占全球制药市场的300亿美元，这些市场在2005年被称为五种含有量的综合式含量。 （PKSS）。 I型PKS，当前研究的目标具有模块化体系结构。 PKS的晶体结构的确定将极大地有助于系统地探索系统的架构特征，并将关键洞察力带入关键特征，例如域边界和底物选择性。反过来，这将允许通过蛋白质工程或底物工程来修改PKS，从而生产下一代的“非天然”聚酮化合物产品。在最近的过去，我们已经解决了6-脱氧于6-脱氧的B-合酶（6-DEB）的194 kDa同型二聚体片段，除了来自6-debs和picromycin picromycin polyketide合成酶的两个硫代酯酶的晶体结构以及Zhuhus priming priming priming synthase synthase synthase synthase（ZHUHUH）的晶体结构外，利用SSRL的Beamtime。 鉴于聚酮化合物在合成有机化学和药物发现中的重要性，求解这些蛋白质的晶体结构仅是利用PKS的基于结构的药物设计的开始，其最终目标是获得各种合成类似物，这些合成类似物将用作巨型药物铅的库。在我们对这些蛋白质结构的研究继续进行的研究中，SSRL的Beamtime将用于解决酮合酶（KS） - 酰基载体蛋白（ACP）蛋白片段的晶体结构，这些蛋白（ACP）蛋白片段将通过来自模块3 Debs的2个单个结构域的不可逆交叉链接获得。