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

Xinlin Hu, Ping Yang, Changdong Chai, Jia Liu, Huanhuan Sun, Yanan Wu, Mingjie Zhang, Min Zhang (), Xiaotian Liu () and Hongjun Yu ()
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Xinlin Hu: Huazhong University of Science and Technology
Ping Yang: Huazhong University of Science and Technology
Changdong Chai: Huazhong University of Science and Technology
Jia Liu: Huazhong University of Science and Technology
Huanhuan Sun: Huazhong University of Science and Technology
Yanan Wu: Huazhong University of Science and Technology
Mingjie Zhang: Southern University of Science and Technology
Min Zhang: Huazhong University of Science and Technology
Xiaotian Liu: Southern University of Science and Technology
Hongjun Yu: Huazhong University of Science and Technology

Nature, 2023, vol. 616, issue 7955, 190-198

Abstract: Abstract The membrane-integrated synthase FKS is involved in the biosynthesis of β-1,3-glucan, the core component of the fungal cell wall1,2. FKS is the target of widely prescribed antifungal drugs, including echinocandin and ibrexafungerp3,4. 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.

Date: 2023
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DOI: 10.1038/s41586-023-05856-5

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