Ring A of Nukacin ISK-1: A Lipid II-Binding Motif for Type-A(II) Lantibiotic
Ring A of Nukacin ISK-1: A Lipid II-Binding Motif for Type-A(II) Lantibiotic
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DOI：
10.1021/ja300007h
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发表时间：
2012-02-29
影响因子：
15
通讯作者：
Sonomoto, Kenji
中科院分区：
文献类型：
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作者：
Islam, Mohammad R.;Nishie, Mami;Sonomoto, Kenji
也存在于不同的A（II）型羊毛硫抗生素中的奴卡星ISK-1的环A类似于脂质II结合基序（TxS/TxD/EC，x表示未定义的残基），其类似于存在于mersacidin（B型羊毛硫抗生素）中的基序，这表明奴卡星ISK-1作为对接分子与脂质II结合。我们的肽聚糖前体（UDP-MurNAc-pp）积累和肽拮抗试验的结果清楚地表明，nukacin ISK-1抑制细胞壁生物合成，在细胞内积累脂质II前体，肽活性可被脂质I和脂质II抑制。努卡星ISK-1和不同的A环变体与脂质II的相互作用分析表明，努卡星ISK-1和努卡星D13 E（更活跃的变体）具有高亲和力（K-D分别为0.17和0.19 μ M），而nukacin D13 A（活性较低的变体）显示出较低的亲和力，而nukacin C14 S（缺乏环A结构的阴性变体）没有表现出相互作用。因此，在此区域中的氨基酸的结构相似性和位置意义的基础上，我们得出结论，nukacin ISK-1通过其环A区域结合脂质II，并可能导致细胞壁生物合成的抑制。
Ring A of nukacin ISK-1, which is also present in different type-A(II) lantibiotics, resembles a lipid II-binding motif (TxS/TxD/EC, x denotes undefined residues) similar to that present in mersacidin (type-B lantibiotics), which suggests that nukacin ISK-1 binds to lipid II as a docking molecule. Results from our experiments on peptidoglycan precursor (UDP-MurNAc-pp) accumulation and peptide antagonism assays clearly indicated that nukacin ISK-1 inhibits cell-wall biosynthesis, accumulating lipid II precursor inside the cell, and the peptide activity can be repressed by lipid I and lipid II. Interaction analysis of nukacin ISK-1 and different ring A variants with lipid II revealed that nukacin ISK-1 and nukacin D13E (a more active variant) have a high affinity (K-D = 0.17 and 0.19 mu M, respectively) for lipid II, whereas nukacin D13A (a less active variant) showed a lower affinity, and nukacin C14S (a negative variant lacking the ring A structure) exhibited no interaction. Therefore, on the basis of the structural similarity and positional significance of the amino acids in this region, we concluded that nukacin ISK-1 binds lipid II via its ring A region and may lead to the inhibition of cell-wall biosynthesis.