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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Published in:Nature (London) Vol. 616; no. 7955; pp. 190 - 198
Main Authors: Hu, Xinlin, Yang, Ping, Chai, Changdong, Liu, Jia, Sun, Huanhuan, Wu, Yanan, Zhang, Mingjie, Zhang, Min, Liu, Xiaotian, Yu, Hongjun
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 06.04.2023
Nature Publishing Group
Subjects:
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631/535/1258/1259
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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
Online Access:Get full text
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Summary: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.
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ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-023-05856-5