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Publication Abstract from PubMed

FKS1 is a beta-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 beta-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 beta-1,3-glucan biosynthesis. Collectively, our findings identify both tRNA and GSR1 as intrinsic modulators of beta-1,3-glucan biosynthesis, thereby providing opportunities for the further development of FKS1-targeted antifungal drugs.

Structural-guided identification of two modulators of beta-1,3-glucan synthase FKS1.,Li J, Li J, Zhu A, Dai X, Liu J, Liu H, Xia Z, Dong Y, Qian W, Dai L, Guo L, Yan C, Deng D, Luo Y, Wang X Nat Commun. 2025 Dec 7. doi: 10.1038/s41467-025-67293-4. PMID:41354657^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.