Structural insights into inhibition of lipid I production in bacterial cell wall synthesis.
Structural insights into inhibition of lipid I production in bacterial cell wall synthesis.
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DOI：
10.1038/nature17636
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发表时间：
2016-05-26
期刊：
影响因子：
64.8
通讯作者：
Lee SY
中科院分区：
文献类型：
--
作者：
Chung BC;Mashalidis EH;Tanino T;Kim M;Matsuda A;Hong J;Ichikawa S;Lee SY
抗生素耐药细菌感染严重威胁公众健康。肽聚糖生物合成是抗生素开发的一个既定目标。 MraY（磷酸-MurNAc-五肽转位酶）催化肽聚糖生物合成的第一步，也是一个重要的膜步骤。它被认为是开发新抗生素的一个非常有前途的目标，因为许多具有抗菌活性的天然核苷抑制剂都以这种酶为目标。然而，针对MraY的抗生素尚未开发用于临床使用，主要是由于缺乏对该酶抑制的结构了解。在这里，我们展示了来自 Aquifex aeolicus (MraYAA) 的 MraY 与其天然抑制剂 Muraymycin D2 (MD2) 的复合物的晶体结构。结合 MD2 后，MraYAA 在活性位点附近经历非常大的构象重排，从而形成核苷结合袋和肽结合位点。 MD2 与核苷结合袋结合，就像插入插座的双管插头一样。它在相邻的肽结合位点中产生额外的相互作用，将 MD2 锚定到 MraYAA 并增强其对 MraYAA 的亲和力。令人惊讶的是，MD2 不与催化所需的三个酸性残基或 Mg2+ 辅因子相互作用，这表明 MD2 与 MraYAA 的结合方式与其天然底物 UDP-MurNAc-五肽重叠但又不同。我们已经破译了 MD2 与 MraYAA 结合的化学逻辑，包括它如何避免对焦磷酸和糖部分的需要，而焦磷酸和糖部分是底物结合的基本特征。 MraY 的构象可塑性可能是它成为许多结构不同抑制剂的靶标的原因。这些发现可以为针对 MraY 及其旁系同源物 WecA 和 TarO 的新抑制剂的设计提供信息。
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) catalyzes 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 occuring nucleoside inhibitors with antibacterial activity target this enzyme. However, antibiotics targeting MraY have not been developed for clinical use mainly due to a lack of structural insight into inhibition of this enzyme. Here we present the crystal structure of MraY from Aquifex aeolicus (MraYAA) in complex with its naturally occurring inhibitor, muraymycin D2 (MD2). Upon 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. Additional 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 deciphered the chemical logic 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 paralogs, WecA and TarO.