Scientists Unveil Structures Revealing How Antifungal Drugs Inhibit Fungal Enzyme

Scientists have solved cryo-electron microscopy structures of native Saccharomyces cerevisiae Fks1 (ScFks1) under catalytically relevant conditions, revealing interactions with the antifungal caspofungin (CFN), glucan product from the translocation channel, and Rho1, @Nature reported.

The structures show CFN forming a ternary complex with nascent glucan and Fks1 at the membrane–protein interface. A separate cryo-electron microscopy structure of the echinocandin-resistant S643P ScFks1 was also determined, indicating that the S643P substitution destabilizes CFN and glucan binding through allosteric structural perturbation and direct steric clash.

Rho1 binding induces active site rearrangements essential for catalysis, including that of the ‘latch loop’ for donor substrate coordination. Additionally, YMR295C was identified as an auxiliary subunit of β-1,3-d-glucan synthase (GS). GS, which comprises the catalytic Fks1 and the regulatory small GTPase Rho1, is the target of clinically important echinocandin antifungals.

Invasive fungal infections pose life-threatening risks to the increasing population of immunocompromised patients. Treatment of these infections remains challenging due to limited antifungal drugs and increasing resistance. An article titled 'Inhibition mechanism of the fungal β−1,3-glucan synthases by triterpenoid antifungal drugs' was published open access on 04 February 2026.