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Dynamic thiolation-thioesterase structure of a non-ribosomal peptide synthetase

机译：非核糖体肽合成酶的动态巯基化-硫酯酶结构

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摘要

Non-ribosomal peptide synthetases (NRPS) and polyketide synthases (PKS) produce numerous secondary metabolites with various therapeutic/antibiotic properties. Like fatty acid synthases (FAS), these enzymes are organized in modular assembly lines in which each module, made of conserved domains, incorporates a given monomer unit into the growing chain. Knowledge about domain or module interactions may enable reengineering of this assembly line enzymatic organization and open avenues for the design of new bioactive compounds with improved therapeutic properties. So far, little structural information has been available on how the domains interact and communicate. This may be because of inherent interdomain mobility hindering crystallization, or because crystallized molecules may not represent the active domain orientations. In solution, the large size and internal dynamics of multidomain fragments (>35 kilodaltons) make structure determination by nuclear magnetic resonance a challenge and require advanced technologies. Here we present the solution structure of the apo-thiolation-thioesterase (T-TE) di-domain fragment of the Escherichia coli enterobactin synthetase EntF NRPS subunit. In the holoenzyme, the T domain carries the growing chain tethered to a 4'-phosphopantetheine whereas the TE domain catalyses hydrolysis and cyclization of the iron chelator enterobactin. The T-TE di-domain forms a compact but dynamic structure with a well-defined domain interface; the two active sites are at a suitable distance for substrate transfer from T to TE. We observe extensive interdomain and intradomain motions for well-defined regions and show that these are modulated by interactions with proteins that participate in the biosynthesis. The T-TE interaction described here provides a model for NRPS, PKS and FAS function in general as T-TE-like di-domains typically catalyse the last step in numerous assembly-line chain-termination machineries.
机译：非核糖体肽合成酶（NRPS）和聚酮化合物合成酶（PKS）会产生许多具有各种治疗/抗生素特性的次级代谢产物。像脂肪酸合酶（FAS）一样，这些酶以模块化组装线形式进行组织，其中每个由保守结构域组成的模块都将给定的单体单元整合到生长链中。关于域或模块相互作用的知识可以使该组装线酶促结构的再工程成为可能，并且为设计具有改善的治疗性质的新生物活性化合物开辟道路。到目前为止，关于域如何交互和通信的结构信息很少。这可能是由于固有的畴间迁移性阻碍了结晶，或者是因为结晶的分子可能不代表活性畴的取向。在解决方案中，多域片段（> 35千道尔顿）的大尺寸和内部动力学使通过核磁共振确定结构成为挑战，并需要先进的技术。在这里，我们介绍了大肠杆菌肠杆菌素合成酶EntF NRPS亚基的脱硫基硫代-硫酯酶（T-TE）双结构域片段的溶液结构。在全酶中，T结构域带有束缚在4'-磷酸泛素上的增长链，而TE结构域则催化铁螯合剂肠杆菌素的水解和环化。 T-TE di-domain形成了紧凑而动态的结构，并具有定义明确的域接口；两个活性位点之间的距离适合于底物从T转移到TE。我们观察到明确定义区域广泛的域间和域内运动，并表明这些受到与参与生物合成的蛋白质相互作用的调节。此处描述的T-TE相互作用通常为NRPS，PKS和FAS功能提供了一个模型，因为T-TE样双结构域通常催化众多组装线链终止设备中的最后一步。

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