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，具有多种药理相关活性，包括抗癌、抗生素、抗病毒和免疫抑制特性，2005 年占全球医药市场价值 300 亿美元。通过称为聚酮化合物合酶（PKS）的多功能蛋白质从有限的简单羧酸库中提取自然。当前研究的目标 I 型 PKS 具有模块化架构。 PKS 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，并产生对域边界和基底选择性等关键特征的重要见解。这反过来又允许通过蛋白质工程或底物工程对 PKS 进行修饰，以生产下一代“非天然”聚酮化合物产品。最近，我们解析了 6-脱氧赤酮内酯 B 合酶（6-DEBS）的 194 kDa 同二聚体片段的晶体结构，以及分别来自 6-DEBS 和picromycin 聚酮化合物合酶的两种硫酯酶的晶体结构以及晶体结构。来自 R1128 聚酮化合物合酶的引发酮合酶 (ZhuH) 的结构先前利用 SSRL 的射束时间求解。 鉴于聚酮化合物在合成有机化学和药物发现中的重要性，解决这些蛋白质的晶体结构只是利用 PKS 进行基于结构的药物设计的开始，最终目标是获得各种合成类似物作为库大环药物先导化合物。继续我们对这些蛋白质结构的研究，SSRL 的 Beamtime 将用于解析酮合酶 (KS)-酰基载体蛋白 (ACP) 蛋白质片段的晶体结构，该片段将通过不可逆共价交联获得来自模块 3 DEBS 的 2 个单独域。