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摘要 : 肽聚糖生物合成是抗生素的一个明确目标。

 肽聚糖生物合成是抗生素的一个明确目标。这一过程的第一步是被MraY催化的,该物质有很多天然出现的抑制剂,但以这种酶为目标的新化合物的设计因对抑制模式的结构认识的缺乏而一直受阻。在这项研究中,Seok-Yong Lee 及同事获得了来自极端嗜热菌Aquifex aeolicus、与自然出现的核苷抑制剂 “muraymycin D2” (MD2)形成复合物的MraY的晶体结构。该结构显示,MraY在MD2结合之后在活性点附近发生很大构形重排,导致一个核苷结合袋 (nucleoside-binding pocket)和一个肽结合点 (peptide-binding site)的生成。


Structural insights into inhibition of lipid I production in bacterial cell wall synthesis


Antibiotic-resistant bacterial infection is a serious threat to public health. Peptidoglycan biosynthesis is a well-established target for antibiotic development. MraY (phospho-MurNAc-pentapeptide translocase) catalyses the first and an essential membrane step of peptidoglycan biosynthesis. It is considered a very promising target for the development of new antibiotics, as many naturally occurring nucleoside inhibitors with antibacterial activity target this enzyme. However, antibiotics targeting MraY have not been developed for clinical use, mainly owing to a lack of structural insight into inhibition of this enzyme. Here we present the crystal structure of MraY fromAquifex aeolicus (MraYAA) in complex with its naturally occurring inhibitor, muraymycin D2 (MD2). We show that after binding MD2, MraYAA undergoes remarkably large conformational rearrangements near the active site, which lead to the formation of a nucleoside-binding pocket and a peptide-binding site. MD2 binds the nucleoside-binding pocket like a two-pronged plug inserting into a socket. Further interactions it makes in the adjacent peptide-binding site anchor MD2 to and enhance its affinity for MraYAA. Surprisingly, MD2 does not interact with three acidic residues or the Mg2+ cofactor required for catalysis, suggesting that MD2 binds to MraYAA in a manner that overlaps with, but is distinct from, its natural substrate, UDP-MurNAc-pentapeptide. We have determined the principles of MD2 binding to MraYAA, including how it avoids the need for pyrophosphate and sugar moieties, which are essential features for substrate binding. The conformational plasticity of MraY could be the reason that it is the target of many structurally distinct inhibitors. These findings can inform the design of new inhibitors targeting MraY as well as its paralogues, WecA and TarO.

来源: Nature 浏览次数:0


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