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Structure paper

TitleStructural basis of fungal β-1,3-glucan synthase inhibition by caspofungin.
Journal, issue, pagesNature, Year 2026
Publish dateApr 22, 2026
AuthorsZhenning Ren / Abhishek Chhetri / Chang Liu / ShuYu Offner / Kedar Sharma / Mario J Borgnia / Wonpil Im / Kenichi Yokoyama / Seok-Yong Lee /
PubMed AbstractInvasive fungal infections pose life-threatening risks to the increasing population of immunocompromised patients. Treatment remains challenging due to limited antifungal drugs and increasing ...Invasive fungal infections pose life-threatening risks to the increasing population of immunocompromised patients. Treatment remains challenging due to limited antifungal drugs and increasing resistance. β-1,3-D-glucan synthase (GS), comprising the catalytic Fks1 and the regulatory small GTPase, Rho1 (refs. ), is the target of clinically important echinocandin antifungals. Despite recent studies, the mechanisms of GS catalysis, Rho1 regulation and echinocandin inhibition and resistance remain elusive. Here we present cryo-electron microscopy structures of native Saccharomyces cerevisiae Fks1 (ScFks1) solved under catalytically relevant conditions, revealing its interactions with the antifungal caspofungin (CFN), glucan product from the translocation channel and Rho1. CFN forms a ternary complex with nascent glucan and Fks1 at the membrane-protein interface, suggesting an unexpected role of CFN in stalling polymer translocation. Our echinocandin-resistant S643P structure suggests a resistance mechanism: the substitution destabilizes CFN and glucan binding through both 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. Furthermore, we identify YMR295C as an auxiliary subunit. These findings elucidate the mechanisms of GS-mediated glucan synthesis and its inhibition and resistance by echinocandins, laying the groundwork for rational antifungal design.
External linksNature / PubMed:42020744
MethodsEM (single particle)
Resolution2.69 - 3.5 Å
Structure data

71550

9pe1

EMDB-71550, PDB-9pe1:
Structure of beta-1,3-glucan synthase in complex with caspofungin, Rho1 and long glucan
Method: EM (single particle) / Resolution: 3.09 Å

71551

9pe2

EMDB-71551, PDB-9pe2:
Structure of beta-1,3-glucan synthase from Saccharomyces cerevisiae (ScFks1) in complex with short glucan
Method: EM (single particle) / Resolution: 3.07 Å

71552

9pe3

EMDB-71552, PDB-9pe3:
Structure of beta-1,3-glucan synthase from Saccharomyces cerevisiae (ScFks1) at the catalytically relevant ground state
Method: EM (single particle) / Resolution: 3.26 Å

71553

9pe4

EMDB-71553, PDB-9pe4:
Structure of beta-1,3-glucan synthase from Saccharomyces cerevisiae (ScFks1) at the catalytically less relevant L2 state
Method: EM (single particle) / Resolution: 2.69 Å

71554

9pe5

EMDB-71554, PDB-9pe5:
Structure of beta-1,3-glucan synthase from Saccharomyces cerevisiae (ScFks1) at the catalytically less relevant L1 state
Method: EM (single particle) / Resolution: 2.8 Å

74746

9ztc

EMDB-74746, PDB-9ztc:
Beta-1,3-glucan synthase Fks1 S643P from Saccharomyces Cerevisiae
Method: EM (single particle) / Resolution: 3.5 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM

ChemComp-UDP:
URIDINE-5'-DIPHOSPHATE / UDP*YM

ChemComp-GSP:
5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE


PDB Unreleased entry

PDB-1chr: Unknown entry

ChemComp-HOH:
WATER

ChemComp-LMN:
Lauryl Maltose Neopentyl Glycol / detergent*YM

Source
  • saccharomyces cerevisiae (brewer's yeast)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / Enzyme / glucan synthesis

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