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TitleStructural-guided identification of two modulators of β-1,3-glucan synthase FKS1.
Journal, issue, pagesNat Commun, Year 2025
Publish dateDec 7, 2025
AuthorsJialu Li / Jian Li / Angqi Zhu / Xinli Dai / Juxiu Liu / Huayi Liu / Zhili Xia / Yuefan Dong / Wenyu Qian / Lunzhi Dai / Li Guo / Chuangye Yan / Dong Deng / Yunzi Luo / Xiang Wang /
PubMed AbstractFKS1 is a β-1,3-glucan synthase critical for fungal cell wall formation and a target for antifungal drugs such as echinocandin and ibrexafungerp. However, the mechanisms regulating FKS1 activity ...FKS1 is a β-1,3-glucan synthase critical for fungal cell wall formation and a target for antifungal drugs such as echinocandin and ibrexafungerp. However, the mechanisms regulating FKS1 activity remain largely unknown. Here, we reveal that transfer RNA (tRNA) acts as an endogenous inhibitor, whereas GSR1 functions as a stabilizer of FKS1. The cryo-EM structure of FKS1 adopts a tRNA-mediated homodimer configuration, representing a quiescent state of β-1,3-glucan synthase. Unexpectedly, the copurified endogenous tRNA is identified as a potent inhibitor that suppresses FKS1 activity. Moreover, high-resolution cryo-EM density analysis enable the identification of GSR1 as an additional binding partner of FKS1. Mutagenesis experiments confirm the interaction between FKS1 and GSR1. Evolutionarily conserved GSR1 is found to increase the stability of FKS1 in β-1,3-glucan biosynthesis. Collectively, our findings identify both tRNA and GSR1 as intrinsic modulators of β-1,3-glucan biosynthesis, thereby providing opportunities for the further development of FKS1-targeted antifungal drugs.
External linksNat Commun / PubMed:41354657
MethodsEM (single particle)
Resolution2.72 - 2.96 Å
Structure data

64501

9utu

EMDB-64501, PDB-9utu:
Structure of Fks1 in complex with YMR295C
Method: EM (single particle) / Resolution: 2.72 Å

64502

9utw

EMDB-64502, PDB-9utw:
Structure of dimeric FKS1 in complex with tRNA
Method: EM (single particle) / Resolution: 2.96 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-DD9:
nonane

ChemComp-D10:
DECANE

ChemComp-HP6:
HEPTANE

ChemComp-XKP:
(11R,14S)-17-amino-14-hydroxy-8,14-dioxo-9,13,15-trioxa-14lambda~5~-phosphaheptadecan-11-yl decanoate

ChemComp-PEF:
DI-PALMITOYL-3-SN-PHOSPHATIDYLETHANOLAMINE / phospholipid*YM

ChemComp-PLM:
PALMITIC ACID

ChemComp-DCR:
icosanoic acid

Source
  • Saccharomyces cerevisiae 'var. diastaticus' (brewer's yeast)
  • saccharomyces cerevisiae (brewer's yeast)
KeywordsMEMBRANE PROTEIN / MEMBRANE PROTEIN-RNA COMPLEX

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