{"title":"Mechanisms of aureobasidin A inhibition and drug resistance in a fungal IPC synthase complex","authors":"Xinyue Wu, Xin Gong, Tian Xie","doi":"10.1038/s41467-025-60423-y","DOIUrl":null,"url":null,"abstract":"<p>The enzyme inositol phosphorylceramide (IPC) synthase is essential for survival and virulence in fungi, while absent in mammals, thus representing a potential target for antifungal treatments. Aureobasidin A (AbA), a natural cyclic peptide, displays antifungal activity and inhibits IPC synthase, but the precise molecular mechanism remains unclear. Here, we present the cryo-EM structure of the <i>Saccharomyces cerevisiae</i> IPC synthase, composed of catalytic subunit Aur1 and regulatory subunit Kei1, in its AbA-bound state. The complex is resolved as a dimer of Aur1-Kei1 heterodimers, with Aur1 mediating homodimerization. AbA occupies a predominantly hydrophobic pocket in the catalytic core domain of each Aur1 subunit, blocking the entry of both substrates. Mutations conferring AbA resistance cluster near the AbA-binding site, thus interfering with AbA binding. Our study lays a foundation for the development of therapeutic drugs targeting fungal IPC synthase.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"87 1","pages":""},"PeriodicalIF":14.7000,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-025-60423-y","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
The enzyme inositol phosphorylceramide (IPC) synthase is essential for survival and virulence in fungi, while absent in mammals, thus representing a potential target for antifungal treatments. Aureobasidin A (AbA), a natural cyclic peptide, displays antifungal activity and inhibits IPC synthase, but the precise molecular mechanism remains unclear. Here, we present the cryo-EM structure of the Saccharomyces cerevisiae IPC synthase, composed of catalytic subunit Aur1 and regulatory subunit Kei1, in its AbA-bound state. The complex is resolved as a dimer of Aur1-Kei1 heterodimers, with Aur1 mediating homodimerization. AbA occupies a predominantly hydrophobic pocket in the catalytic core domain of each Aur1 subunit, blocking the entry of both substrates. Mutations conferring AbA resistance cluster near the AbA-binding site, thus interfering with AbA binding. Our study lays a foundation for the development of therapeutic drugs targeting fungal IPC synthase.
肌醇磷酸化神经酰胺（IPC）合成酶对真菌的生存和毒力至关重要，而在哺乳动物中不存在，因此代表了抗真菌治疗的潜在靶点。Aureobasidin A （AbA）是一种天然环状肽，具有抗真菌活性并抑制IPC合酶，但其确切的分子机制尚不清楚。在此，我们展示了由催化亚基Aur1和调控亚基Kei1组成的酿酒酵母IPC合成酶在aba结合状态下的低温电镜结构。该配合物被分解为Aur1- kei1异源二聚体的二聚体，Aur1介导同二聚。AbA在每个Aur1亚基的催化核心区域占据一个主要的疏水性口袋，阻止两种底物的进入。具有AbA抗性的突变聚集在AbA结合位点附近，从而干扰AbA结合。本研究为开发针对真菌IPC合酶的治疗药物奠定了基础。
期刊介绍：
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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