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- PDB-9pe1: Structure of beta-1,3-glucan synthase in complex with caspofungin... -

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Basic information

Entry
Database: PDB / ID: 9pe1
TitleStructure of beta-1,3-glucan synthase in complex with caspofungin, Rho1 and long glucan
Components
  • 1,3-beta-glucan synthase component FKS1
  • Caspofungin
  • GTP-binding protein RHO1
  • Gsr1p
KeywordsMEMBRANE PROTEIN / Enzyme / glucan synthesis
Function / homology
Function and homology information


regulation of secondary cell septum biogenesis / PI3K/AKT activation / G beta:gamma signalling through PI3Kgamma / RHO GTPases activate PKNs / RND3 GTPase cycle / cellular bud neck septin ring organization / G alpha (12/13) signalling events / RHOF GTPase cycle / RND1 GTPase cycle / positive regulation of mitotic actomyosin contractile ring assembly ...regulation of secondary cell septum biogenesis / PI3K/AKT activation / G beta:gamma signalling through PI3Kgamma / RHO GTPases activate PKNs / RND3 GTPase cycle / cellular bud neck septin ring organization / G alpha (12/13) signalling events / RHOF GTPase cycle / RND1 GTPase cycle / positive regulation of mitotic actomyosin contractile ring assembly / regulation of cell wall (1->3)-beta-D-glucan biosynthetic process / regulation of exocyst localization / : / RND2 GTPase cycle / budding cell bud growth / RHOC GTPase cycle / regulation of fungal-type cell wall organization / spore wall / fungal-type cell wall polysaccharide biosynthetic process / 1,3-beta-glucan synthase / 1,3-beta-D-glucan synthase activity / regulation of vacuole fusion, non-autophagic / (1->3)-beta-D-glucan biosynthetic process / : / 1,3-beta-D-glucan synthase complex / RHOA GTPase cycle / fungal-type cell wall biogenesis / cellular bud / ascospore wall assembly / incipient cellular bud site / actin cortical patch / cellular bud tip / fungal-type cell wall / cellular bud neck / mating projection tip / fungal-type vacuole membrane / peroxisomal membrane / regulation of cell size / small GTPase-mediated signal transduction / positive regulation of endocytosis / Neutrophil degranulation / small monomeric GTPase / actin filament organization / cell periphery / regulation of actin cytoskeleton organization / enzyme activator activity / peroxisome / regulation of protein localization / G-protein beta-subunit binding / actin cytoskeleton organization / G protein activity / mitochondrial outer membrane / endosome membrane / GTPase activity / protein kinase binding / GTP binding / endoplasmic reticulum / Golgi apparatus / signal transduction / mitochondrion / membrane / plasma membrane / cytosol
Similarity search - Function
Protein of unknown function DUF2406 / Uncharacterised protein (DUF2406) / : / 1,3-beta-glucan synthase component FKS1, second domain / Glycosyl transferase, family 48 / 1,3-beta-glucan synthase subunit FKS1-like, domain-1 / 1,3-beta-glucan synthase component / 1,3-beta-glucan synthase subunit FKS1, domain-1 / 1,3-beta-glucan synthase subunit FKS1 / Small GTPase Rho ...Protein of unknown function DUF2406 / Uncharacterised protein (DUF2406) / : / 1,3-beta-glucan synthase component FKS1, second domain / Glycosyl transferase, family 48 / 1,3-beta-glucan synthase subunit FKS1-like, domain-1 / 1,3-beta-glucan synthase component / 1,3-beta-glucan synthase subunit FKS1, domain-1 / 1,3-beta-glucan synthase subunit FKS1 / Small GTPase Rho / Small GTPase Rho domain profile. / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
1,2-Distearoyl-sn-glycerophosphoethanolamine / : / 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE / URIDINE-5'-DIPHOSPHATE / CHOLESTEROL HEMISUCCINATE / GTP-binding protein RHO1 / 1,3-beta-glucan synthase component FKS1 / Uncharacterized protein YMR295C
Similarity search - Component
Biological speciesSaccharomyces cerevisiae (brewer's yeast)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsRen, Z. / Lee, S.Y.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI170906 United States
CitationJournal: Nature / Year: 2026
Title: Structural basis of fungal β-1,3-glucan synthase inhibition by caspofungin.
Authors: Zhenning Ren / Abhishek Chhetri / Chang Liu / ShuYu Offner / Kedar Sharma / Mario J Borgnia / Wonpil Im / Kenichi Yokoyama / Seok-Yong Lee /
Abstract: Invasive 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.
History
DepositionJul 1, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 1,3-beta-glucan synthase component FKS1
E: GTP-binding protein RHO1
G: Gsr1p
H: Caspofungin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)290,45040
Polymers270,4814
Non-polymers19,96936
Water1629
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 3 molecules AEG

#1: Protein 1,3-beta-glucan synthase component FKS1 / 1 / 3-beta-D-glucan-UDP glucosyltransferase / Calcineurin dependent protein 1 / Calcofluor white ...1 / 3-beta-D-glucan-UDP glucosyltransferase / Calcineurin dependent protein 1 / Calcofluor white hypersensitivity protein 53 / Echinocandin target gene protein 1 / FK506 sensitivity protein 1 / Glucan synthase of cerevisiae protein 1 / Papulacandin B resistance protein 1


Mass: 221252.484 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P38631, 1,3-beta-glucan synthase
#2: Protein GTP-binding protein RHO1 / Rho-type GTPase 1


Mass: 26145.652 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: RHO1, YPR165W, P9325.3 / Production host: Escherichia coli (E. coli) / References: UniProt: P06780, small monomeric GTPase
#3: Protein Gsr1p


Mass: 22209.684 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: Q03559

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Protein/peptide , 1 types, 1 molecules H

#4: Protein/peptide Caspofungin


Mass: 872.920 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Sugars , 3 types, 3 molecules

#5: Polysaccharide beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D- ...beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose-(1-3)-beta-D-glucopyranose


Type: oligosaccharide / Mass: 2774.409 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-3DGlcpb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,17,16/[a2122h-1b_1-5]/1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1-1/a3-b1_b3-c1_c3-d1_d3-e1_e3-f1_f3-g1_g3-h1_h3-i1_i3-j1_j3-k1_k3-l1_l3-m1_m3-n1_n3-o1_o3-p1_p3-q1WURCSPDB2Glycan 1.1.0
[][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{[(3+1)][b-D-Glcp]{}}}}}}}}}}}}}}}}}LINUCSPDB-CARE
#6: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#7: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 6 types, 42 molecules

#8: Chemical...
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 29 / Source method: obtained synthetically / Formula: C31H50O4
#9: Chemical ChemComp-3PE / 1,2-Distearoyl-sn-glycerophosphoethanolamine / 3-SN-PHOSPHATIDYLETHANOLAMINE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE


Mass: 748.065 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C41H82NO8P / Comment: phospholipid*YM
#10: Chemical ChemComp-UDP / URIDINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 404.161 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H14N2O12P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: UDP*YM
#11: Chemical ChemComp-GSP / 5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE


Mass: 539.246 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3S
#12: Chemical ChemComp-A1CHR / (10R,12S)-10,12-dimethyltetradecanoic acid


Mass: 256.424 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H32O2 / Feature type: SUBJECT OF INVESTIGATION
#13: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 9 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Structure of beta-1,3-glucan synthase from Saccharomyces cerevisiae (ScFks1) in CHAPS/CHS at the CFN-Rho1-long-glucan-bound state with UDP bound
Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Source (natural)Organism: Saccharomyces cerevisiae (brewer's yeast)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20.1_4487: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 48860 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00317215
ELECTRON MICROSCOPYf_angle_d0.80523550
ELECTRON MICROSCOPYf_dihedral_angle_d13.8866079
ELECTRON MICROSCOPYf_chiral_restr0.0562731
ELECTRON MICROSCOPYf_plane_restr0.0042812

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