7YUY

Structure of a mutated membrane-bound glycosyltransferase

Summary for 7YUY

• Entry DOI: 10.2210/pdb7yuy/pdb
• Related: 7XE4
• EMDB information: 34115
• Descriptor: 1,3-beta-glucan synthase component FKS1, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: membrane protein, glycosyltransferase, transferase
• Biological source: Saccharomyces cerevisiae (baker's yeast)
• Total number of polymer chains: 1
• Total formula weight: 219835.05

Authors

Hu, X.L.,Yang, P.,Zhang, M.,Liu, X.T.,Yu, H.J. (deposition date: 2022-08-18, release date: 2023-03-29, Last modification date: 2025-06-18)

Primary citation

Hu, X.,Yang, P.,Chai, C.,Liu, J.,Sun, H.,Wu, Y.,Zhang, M.,Zhang, M.,Liu, X.,Yu, H.
Structural and mechanistic insights into fungal beta-1,3-glucan synthase FKS1.
Nature, 616:190-198, 2023

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

PubMed: 36949198
DOI: 10.1038/s41586-023-05856-5

Experimental method

ELECTRON MICROSCOPY (3.5 Å)