Untersuchung der Wechselwirkung von PCP Domänen mit Interaktionspartnern in Nicht-ribosomalen Peptidsynthetasen

PCP 结构域与非核糖体肽合成酶中相互作用伙伴的相互作用的研究

• 批准号: 171029658
• 负责人: Professor Dr. Volker Dötsch
• 金额: --
• 依托单位: Institut für Biophysikalische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/171029658?language=en
• 关键词: Untersuchung; der; Wechselwirkung; von; PCP; Untersuchung; der; Wechselwirkung; von; PCP

Non-ribosomal peptide synthetases (NRPS) constitute a class of large multidomain enzymes found in the cytoplasm of bacteria and fungi that produce a large set of peptides with biological activities ranging from iron sequestration to chemical defense against other microbes. Many of these peptides are used as drugs with antibiotic, anticancer or immunosuppressive activity, making NRPS systems of high medical importance. The modular structure of these NRPS systems has fueled attempts to create new, potentially medically important peptides by combining modules from different NRPS systems into new assembly lines. However, many design experiments have shown that even small changes in the assembly lines result in significant reductions in yield, suggesting that the individual modules are not mere beads on a string but that specific domaindomain interactions play important roles. In previous studies we investigated the interaction of peptide carrier proteins (PCPs) with thioesterases and other intrans interacting enzymes. In this grant application we describe detailed studies of the domain-domain interaction of PCPs with the major components of NRPS systems, the A- and the C-domains that are responsible for amino acids type selection and for performing the chemical condensation step of the reaction. In particular we will focus on the role of peptides that are covalently attached to the PCP and that modulate the interaction with C-domains.

在细菌和真菌的细胞质中发现的一类大型多域酶构成了一类大型多域酶，这些酶产生了一系列的肽，其生物学活性从铁序列到化学防御到其他微生物的生物学活性。这些肽中的许多被用作具有抗生素，抗癌或免疫抑制活性的药物，从而使NRPS系统具有很高的医学重要性。这些NRPS系统的模块化结构通过将不同NRPS系统的模块组合到新的装配线中来创造新的，潜在的医学重要肽。但是，许多设计实验表明，即使是组装线的小变化也会导致产量显着降低，这表明单个模块不仅仅是字符串上的珠子，而是特定的域域相互作用起着重要的作用。在先前的研究中，我们研究了肽载体蛋白（PCP）与硫酯酶和其他插入酶相互作用酶的相互作用。在此赠款应用中，我们描述了PCP与NRPS系统的主要组成部分，负责氨基酸类型选择并执行反应的化学凝结步骤的域域相互作用的详细研究。特别是，我们将重点关注与PCP共价连接并调节与C域相互作用的肽的作用。