Structural and mechanistic insights into fungal β-1,3-glucan synthase FKS1

The membrane-integrated synthase FKS is involved in the biosynthesis of β-1,3-glucan, the core component of the fungal cell wall 1 , 2 . FKS is the target of widely prescribed antifungal drugs, including echinocandin and ibrexafungerp 3 , 4 . Unfortunately, the mechanism of action of FKS remains eni...

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Veröffentlicht in:	Nature (London) Jg. 616; H. 7955; S. 190 - 198
Hauptverfasser:	Hu, Xinlin, Yang, Ping, Chai, Changdong, Liu, Jia, Sun, Huanhuan, Wu, Yanan, Zhang, Mingjie, Zhang, Min, Liu, Xiaotian, Yu, Hongjun
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 06.04.2023 Nature Publishing Group
Schlagworte:	101/28 631/326/193 631/45/221 631/535/1258/1259 82/16 82/80 82/83 Antifungal agents Antifungal Agents - pharmacology beta-Glucans - metabolism Biosynthesis Catalytic Domain Cell Membrane - chemistry Cell Membrane - metabolism Cryoelectron Microscopy Cytoplasm Drug delivery Drug resistance Drug Resistance, Fungal - drug effects Drug Resistance, Fungal - genetics Drugs Echinocandins Echinocandins - pharmacology Electron microscopy Enzymes Fungi Fungicides Glucan Glucosyltransferases - antagonists & inhibitors Glucosyltransferases - chemistry Glucosyltransferases - genetics Glucosyltransferases - metabolism Glucosyltransferases - ultrastructure Humanities and Social Sciences Lipids Membranes Microbial Sensitivity Tests Microscopy multidisciplinary Mutation Polymers Resistant mutant Saccharomyces cerevisiae - drug effects Saccharomyces cerevisiae - enzymology Saccharomyces cerevisiae Proteins - antagonists & inhibitors Saccharomyces cerevisiae Proteins - chemistry Saccharomyces cerevisiae Proteins - genetics Saccharomyces cerevisiae Proteins - metabolism Saccharomyces cerevisiae Proteins - ultrastructure Science Science (multidisciplinary) Translocation β-1,3-Glucan
ISSN:	0028-0836, 1476-4687, 1476-4687
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Zusammenfassung:	The membrane-integrated synthase FKS is involved in the biosynthesis of β-1,3-glucan, the core component of the fungal cell wall 1 , 2 . FKS is the target of widely prescribed antifungal drugs, including echinocandin and ibrexafungerp 3 , 4 . Unfortunately, the mechanism of action of FKS remains enigmatic and this has hampered development of more effective medicines targeting the enzyme. Here we present the cryo-electron microscopy structures of Saccharomyces cerevisiae FKS1 and the echinocandin-resistant mutant FKS1(S643P). These structures reveal the active site of the enzyme at the membrane–cytoplasm interface and a glucan translocation path spanning the membrane bilayer. Multiple bound lipids and notable membrane distortions are observed in the FKS1 structures, suggesting active FKS1–membrane interactions. Echinocandin-resistant mutations are clustered at a region near TM5–6 and TM8 of FKS1. The structure of FKS1(S643P) reveals altered lipid arrangements in this region, suggesting a drug-resistant mechanism of the mutant enzyme. The structures, the catalytic mechanism and the molecular insights into drug-resistant mutations of FKS1 revealed in this study advance the mechanistic understanding of fungal β-1,3-glucan biosynthesis and establish a foundation for developing new antifungal drugs by targeting FKS. Using cryo-electron microscopy, the molecular architecture and catalytic mechanism of action of the fungal β-1,3-glucan synthase FKS1 are determined.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-023-05856-5