Structural-guided identification of two modulators of β−1,3-glucan synthase FKS1
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.
Authors
- Yuefan Dong (ORCID: https://orcid.org/0000-0003-3374-6530)
- Chuangye Yan (ORCID: https://orcid.org/0000-0001-9338-8048)
- Angqi Zhu (ORCID: https://orcid.org/0000-0002-3162-441X)
- Li Guo (ORCID: https://orcid.org/0000-0002-7445-5257)
- Wen-Yu Qian
- Huayi Liu (ORCID: https://orcid.org/0000-0001-5179-1912)
- Juxiu Liu (ORCID: https://orcid.org/0000-0001-7850-1006)
- Yunzi Luo (ORCID: https://orcid.org/0000-0002-5860-6350)
- Zhili Xia
- Lunzhi Dai (ORCID: https://orcid.org/0000-0002-3003-8910)
- Dong Deng (ORCID: https://orcid.org/0000-0002-8590-9525)
- Jian Li (ORCID: https://orcid.org/0000-0002-3167-4265)
- Xiang Wang (ORCID: https://orcid.org/0000-0001-9348-7441)
- Xinli Dai
- Jialu Li (ORCID: https://orcid.org/0000-0002-0513-7597)
Institutions
- Northeast Normal University (CN)
- Sichuan University (CN)
- King Center (US)
- West China Second University Hospital of Sichuan University (CN)
- Tianjin Synthetic Material Research Institute (China) (CN)
- Intelligent Synthetic Biology Center (KR)
- State Key Laboratory of Synthetic Chemistry (CN)
- Center for Life Sciences (CN)
- First Hospital of Lanzhou University (CN)
- State Key Laboratory of Biotherapy
- Lanzhou University (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-07
- DOI
- https://doi.org/10.1038/s41467-025-67293-4
- Citations
- 1
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 0.81