Structural Insights into Thioether Bond Formation in the Biosynthesis of Sactipeptides.
Structural Insights into Thioether Bond Formation in the Biosynthesis of Sactipeptides.
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DOI：
10.1021/jacs.7b01283
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发表时间：
2017-08-30
影响因子：
15
通讯作者：
Bowers AA
中科院分区：
文献类型：
--
作者：
Grove TL;Himes PM;Hwang S;Yumerefendi H;Bonanno JB;Kuhlman B;Almo SC;Bowers AA
乳糖肽是核糖体合成的肽，其含有特征性的硫醚桥（sactionine bond），该硫醚桥在后序安装并且是其抗生素活性绝对需要的。乳糖肽生物合成需要一个独特的自由基SAM酶家族，其包含多个[4Fe-4S]簇，以通过基于自由基的化学在半胱氨酸和相对氨基酸的α-碳之间形成必需的硫醚桥。在这里，我们提出了结构的sactionine键形成酶CteB，从热纤梭菌ATCC 27405，与SAM和其肽基底物的N-末端片段在2.04 nm分辨率。CteB具有（β/α）6-TIM桶折叠，这是自由基SAM酶的特征，以及C-末端SPASM结构域，其包含两个辅助[4Fe-4S]簇。重要的是，SPASM结构域中的一个[4Fe-4S]簇在不存在肽底物的情况下表现出开放的配位位点，其由结合状态下的肽基-半胱氨酸残基配位。CteB的晶体结构还揭示了一个附属的N-末端结构域，该结构域与最近发现的作用于核糖体合成和后修饰肽（RiPP）的几种酶中存在的基序具有高度的结构相似性，该基序被称为RiPP前体肽识别元件（RRE）。这种晶体结构是第一个形成糖精键的酶，并揭示了这类其他成员的结构和机制，如AlbA或ThnB。
Sactipeptides are ribosomally-synthesized peptides that contain a characteristic thioether bridge (sactionine bond) that is installed posttranslationally and is absolutely required for their antibiotic activity. Sactipeptide biosynthesis requires a unique family of radical SAM enzymes, which contain multiple [4Fe-4S] clusters, to form the requisite thioether bridge between a cysteine and the α-carbon of an opposing amino acid through radical-based chemistry. Here we present the structure of the sactionine bond-forming enzyme CteB, from Clostridium thermocellum ATCC 27405, with both SAM and an N-terminal fragment of its peptidyl-substrate at 2.04 Å resolution. CteB has the (β/α)6-TIM barrel fold that is characteristic of radical SAM enzymes, as well as a C-terminal SPASM domain that contains two auxiliary [4Fe-4S] clusters. Importantly, one [4Fe-4S] cluster in the SPASM domain exhibits an open coordination site in absence of peptide substrate, which is coordinated by a peptidyl-cysteine residue in the bound state. The crystal structure of CteB also reveals an accessory N-terminal domain that has high structural similarity to a recently discovered motif present in several enzymes that act on ribosomally-synthesized and post-translationally modified peptides (RiPPs), known as a RiPP precursor peptide recognition element (RRE). This crystal structure is the first of a sactionine bond forming enzyme and sheds light on structures and mechanisms of other members of this class such as AlbA or ThnB.
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