Coenzyme recognition and gene regulation by a flavin mononucleotide riboswitch.
Coenzyme recognition and gene regulation by a flavin mononucleotide riboswitch.
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DOI：
10.1038/nature07642
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发表时间：
2009-03-12
期刊：
影响因子：
64.8
通讯作者：
Patel, Dinshaw J.
中科院分区：
文献类型：
--
作者：
Serganov, Alexander;Huang, Lili;Patel, Dinshaw J.
几种蛋白质辅因子的生物合成受到核糖开关的反馈调节。黄素单核苷酸 (FMN) 特异性核糖开关，也称为 RFN 元件，直接表达参与核黄素（维生素 B2）和相关化合物生物合成和运输的细菌基因。在这里，我们展示了与 FMN、核黄素和抗生素玫瑰黄素结合的具核梭杆菌核糖开关的晶体结构。 FMN 核糖开关结构以 FMN 结合的六茎连接为中心，不会通过相邻螺旋的共线堆叠进行折叠，这是大 RNA 折叠的典型特征。相反，它采用蝴蝶状支架，由方向相反但几乎相同折叠的外围区域缝合在一起。 FMN 不对称地位于连接位点内，通过与异咯嗪环发色团的相互作用以及直接和 Mg2+ 介导的与磷酸基团的接触，与 RNA 特异性结合。我们的结构数据，通过结合和足迹实验进行补充，意味着很大程度上是预折叠的三级RNA结构和由连接结合袋内的构象转变介导的FMN识别。 FMN 结合袋固有的可塑性和大开口的可用性使核糖开关成为基于结构的 FMN 类抗菌化合物设计的有吸引力的目标。我们的研究还解释了自发和抗生素诱导的失调突变的影响，并为正常和核黄素过量产生的细菌菌株中基于 FMN 的基因表达控制提供了分子见解。
The biosynthesis of several protein cofactors is subject to feedback regulation by riboswitches. Flavin mononucleotide (FMN)-specific riboswitches, also known as RFN elements, direct expression of bacterial genes involved in the biosynthesis and transport of riboflavin (vitamin B2) and related compounds. Here we present the crystal structures of the Fusobacterium nucleatum riboswitch bound to FMN, riboflavin and antibiotic roseoflavin. The FMN riboswitch structure, centred on an FMN-bound six-stem junction, does not fold by collinear stacking of adjacent helices, typical for folding of large RNAs. Rather, it adopts a butterfly-like scaffold, stapled together by opposingly directed but nearly identically folded peripheral domains. FMN is positioned asymmetrically within the junctional site and is specifically bound to RNA through interactions with the isoalloxazine ring chromophore and direct and Mg2+-mediated contacts with the phosphate moiety. Our structural data, complemented by binding and footprinting experiments, imply a largely pre-folded tertiary RNA architecture and FMN recognition mediated by conformational transitions within the junctional binding pocket. The inherent plasticity of the FMN-binding pocket and the availability of large openings make the riboswitch an attractive target for structure-based design of FMN-like antimicrobial compounds. Our studies also explain the effects of spontaneous and antibiotic-induced deregulatory mutations and provided molecular insights into FMN-based control of gene expression in normal and riboflavin-overproducing bacterial strains.
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5.6
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