Journal Article

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

Yang, Ping, Sun, Huanhuan, Yu, Hongjun, Zhang, Mingjie, Liu, Xiaotian, Hu, Xinlin, Liu, Jia, Chai, Changdong, Wu, Yanan, Zhang, Min

2023

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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