Drug inhibition of glycosyltransferases Mycobacteria, including the species that causes tuberculosis (TB), synthesize a complex cell wall that helps to support and protect the bacterial cells. The major components of the cell wall include complex heteropolysaccharides that are synthesized in the periplasmic space. Zhang et al. determined the cryo–electron microscopy structures of two transmembrane glycosyltransferase enzyme complexes that use a lipid-anchored sugar donor to append arabinose units to the cell wall polysaccharides. They also captured the anti-TB drug ethambutol bound within these complexes and observed that it binds in a site overlapping both donor and acceptor sugars. Mapping of resistance mutants provides a structural understanding of how resistance emerges while preserving function of the enzyme and may help to guide the development of next-generation anti-TB drugs that target these enzymes. Science, this issue p. 1211 Structures of mycobacterial glycosyltransferases define a binding site for an anti-tuberculosis drug. The arabinosyltransferases EmbA, EmbB, and EmbC are involved in Mycobacterium tuberculosis cell wall synthesis and are recognized as targets for the anti-tuberculosis drug ethambutol. In this study, we determined cryo–electron microscopy and x-ray crystal structures of mycobacterial EmbA-EmbB and EmbC-EmbC complexes in the presence of their glycosyl donor and acceptor substrates and with ethambutol. These structures show how the donor and acceptor substrates bind in the active site and how ethambutol inhibits arabinosyltransferases by binding to the same site as both substrates in EmbB and EmbC. Most drug-resistant mutations are located near the ethambutol binding site. Collectively, our work provides a structural basis for understanding the biochemical function and inhibition of arabinosyltransferases and the development of new anti-tuberculosis agents.

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细胞壁阿拉伯糖基转移酶与抗结核药物乙胺丁醇的结构

糖基转移酶的药物抑制 分枝杆菌，包括导致结核病 (TB) 的物种，合成有助于支持和保护细菌细胞的复杂细胞壁。细胞壁的主要成分包括在周质空间合成的复杂杂多糖。张等人。确定了两种跨膜糖基转移酶复合物的冷冻电子显微镜结构，这些复合物使用脂质锚定糖供体将阿拉伯糖单位附加到细胞壁多糖上。他们还捕获了结合在这些复合物中的抗结核药物乙胺丁醇，并观察到它结合在与供体和受体糖重叠的位点。耐药突变体的定位提供了对耐药性如何在保持酶功能的同时出现的结构性理解，并可能有助于指导针对这些酶的下一代抗结核药物的开发。科学，这个问题 p。1211 分枝杆菌糖基转移酶的结构定义了抗结核药物的结合位点。阿拉伯糖基转移酶 EmbA、EmbB 和 EmbC 参与结核分枝杆菌细胞壁的合成，并被认为是抗结核药物乙胺丁醇的靶标。在这项研究中，我们确定了分枝杆菌 EmbA-EmbB 和 EmbC-EmbC 复合物在存在糖基供体和受体底物以及乙胺丁醇的情况下的冷冻电子显微镜和 X 射线晶体结构。这些结构显示了供体和受体底物如何在活性位点结合，以及乙胺丁醇如何通过与 EmbB 和 EmbC 中的两种底物结合到同一位点来抑制阿拉伯糖基转移酶。大多数耐药突变位于乙胺丁醇结合位点附近。总的来说，我们的工作为理解阿拉伯糖基转移酶的生化功能和抑制作用以及开发新的抗结核药物提供了结构基础。