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- EMDB-73041: cryoEM structure of Aspergillus fumigatus acetolactate synthase (... -

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Basic information

Entry
Database: EMDB / ID: EMD-73041
TitlecryoEM structure of Aspergillus fumigatus acetolactate synthase (ALS) in complex with a novel inhibitor
Map data
Sample
  • Complex: Aspergillus fumigatus Acetolactate synthase
    • Protein or peptide: Acetolactate synthase
  • Ligand: MAGNESIUM ION
  • Ligand: THIAMINE DIPHOSPHATE
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
  • Ligand: (1R,2R,4aR,8R,8aR)-8-[(3S,5R)-5-(3-hydroxypropyl)-2,4-dioxopyrrolidin-3-yl]-3,8-dimethyl-2-propyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carbaldehyde
Keywordsantifungal target / herbicide target / anti fugal infection / natural product / PLANT PROTEIN
Function / homology
Function and homology information


L-isoleucine biosynthetic process / acetolactate synthase / acetolactate synthase complex / acetolactate synthase activity / L-valine biosynthetic process / thiamine pyrophosphate binding / flavin adenine dinucleotide binding / magnesium ion binding / mitochondrion
Similarity search - Function
Acetolactate synthase, large subunit, biosynthetic / Acetolactate synthase large subunit, TPP binding domain / Thiamine pyrophosphate enzyme / TPP-binding enzyme, conserved site / Thiamine pyrophosphate enzymes signature. / Thiamine pyrophosphate enzyme, central domain / Thiamine pyrophosphate enzyme, central domain / Thiamine pyrophosphate enzyme, N-terminal TPP-binding domain / Thiamine pyrophosphate enzyme, N-terminal TPP binding domain / Thiamine pyrophosphate enzyme, C-terminal TPP-binding ...Acetolactate synthase, large subunit, biosynthetic / Acetolactate synthase large subunit, TPP binding domain / Thiamine pyrophosphate enzyme / TPP-binding enzyme, conserved site / Thiamine pyrophosphate enzymes signature. / Thiamine pyrophosphate enzyme, central domain / Thiamine pyrophosphate enzyme, central domain / Thiamine pyrophosphate enzyme, N-terminal TPP-binding domain / Thiamine pyrophosphate enzyme, N-terminal TPP binding domain / Thiamine pyrophosphate enzyme, C-terminal TPP-binding / Thiamine pyrophosphate enzyme, C-terminal TPP binding domain / Thiamin diphosphate-binding fold / DHS-like NAD/FAD-binding domain superfamily
Similarity search - Domain/homology
Acetolactate synthase
Similarity search - Component
Biological speciesAspergillus fumigatus (mold)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.36 Å
AuthorsHu Y
Funding support1 items
OrganizationGrant numberCountry
Other private
CitationJournal: ACS Cent Sci / Year: 2026
Title: An Antifungal with a Novel Mechanism of Action Discovered via Resistance Gene-Guided Genome Mining.
Authors: Bruno Perlatti / Sandeep Vellanki / Yalong Zhang / Yi-Ming Chiang / Yingxia Hu / Mengdi Yuan / Kyle Dunbar / Abigail Fine / Michelle F Grau / Sheena Li / Timothy O'Donnell / Rajani Shenoy / ...Authors: Bruno Perlatti / Sandeep Vellanki / Yalong Zhang / Yi-Ming Chiang / Yingxia Hu / Mengdi Yuan / Kyle Dunbar / Abigail Fine / Michelle F Grau / Sheena Li / Timothy O'Donnell / Rajani Shenoy / Hongtao Li / Hui Shi / Xia Xu / Zeyu Chen / Tara Arvedson / Yi Tang / Robert A Cramer / Victor Cee / Colin J B Harvey /
Abstract: Invasive fungal infections claim over two million lives annually, a problem exacerbated by rising resistance to current antifungal treatments and an increasing population of immunocompromised ...Invasive fungal infections claim over two million lives annually, a problem exacerbated by rising resistance to current antifungal treatments and an increasing population of immunocompromised individuals. Despite this, antifungal drug development has stagnated, with few novel agents and fewer novel targets explored in recent decades. Here, we validate acetolactate synthase (ALS), an enzyme critical for branched-chain amino acid biosynthesis and absent in humans, as a promising target for new therapeutics. Using resistance gene-guided genome mining, we discovered a biosynthetic gene cluster in encoding HB-35018 (1), a novel spiro-cis-decalin tetramic acid that potently inhibits ALS. Biochemical and antifungal assays demonstrate that surpasses existing ALS inhibitors in efficacy against and other pathogenic fungi. Structural studies via cryo-electron microscopy reveal a unique covalent binding interaction between compound and ALS, distinct from known inhibitors, and finally, we demonstrate that ALS is essential for virulence in a mouse model of invasive aspergillosis. These findings position ALS as a promising target for antifungal development and demonstrate the potential of resistance gene-guided genome mining for antifungal discovery.
History
DepositionOct 6, 2025-
Header (metadata) releaseMar 18, 2026-
Map releaseMar 18, 2026-
UpdateMar 18, 2026-
Current statusMar 18, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_73041.png

Downloads & links

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Map

FileDownload / File: emd_73041.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.74 Å/pix.
x 384 pix.
= 285.312 Å		0.74 Å/pix.
x 384 pix.
= 285.312 Å		0.74 Å/pix.
x 384 pix.
= 285.312 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.743 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.32800797 - 0.6371386
Average (Standard dev.)-0.00008038378 (±0.012317208)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 285.31198 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_73041_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_73041_half_map_2.map
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Sample components

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Entire : Aspergillus fumigatus Acetolactate synthase

EntireName: Aspergillus fumigatus Acetolactate synthase
Components
  • Complex: Aspergillus fumigatus Acetolactate synthase
    • Protein or peptide: Acetolactate synthase
  • Ligand: MAGNESIUM ION
  • Ligand: THIAMINE DIPHOSPHATE
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
  • Ligand: (1R,2R,4aR,8R,8aR)-8-[(3S,5R)-5-(3-hydroxypropyl)-2,4-dioxopyrrolidin-3-yl]-3,8-dimethyl-2-propyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carbaldehyde

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Supramolecule #1: Aspergillus fumigatus Acetolactate synthase

SupramoleculeName: Aspergillus fumigatus Acetolactate synthase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Aspergillus fumigatus (mold)
Molecular weightTheoretical: 133 KDa

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Macromolecule #1: Acetolactate synthase

MacromoleculeName: Acetolactate synthase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: acetolactate synthase
Source (natural)Organism: Aspergillus fumigatus (mold)
Molecular weightTheoretical: 70.307812 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SPAFNQEPHR NEVSPLQNRH LPELDDSTSL ITVMSRFVGL SGGQIFHEMM LRLGVKHIFG YPGGAILPVF DAIYNSKHFD FVLPRHEQG AGHMAEGYAR ASGKPGVVLV TSGPGATNVI TPMQDALSDG TPMVVFCGQV PTSSIGTDSF QEADVVGISR A CTKWNVMV ...String:
SPAFNQEPHR NEVSPLQNRH LPELDDSTSL ITVMSRFVGL SGGQIFHEMM LRLGVKHIFG YPGGAILPVF DAIYNSKHFD FVLPRHEQG AGHMAEGYAR ASGKPGVVLV TSGPGATNVI TPMQDALSDG TPMVVFCGQV PTSSIGTDSF QEADVVGISR A CTKWNVMV KSVAELPRRI QEAFEIATSG RPGPVLVDLP KDITAGILRK PIPMNSTIPS LPSAATMAAR ELSMKQLESS ID RVARLVN IAQKPVLYVG QGLLARPDGP KVLKELADKA CIPVTTTLQG LGGFDELDPK ALHMLGMHGS AYANMAMQEA DLI IAVGAR FDDRVTGNLS KFAPQAKLAA SEKRGGIVHF EIMPKNINKV VQANEAVEGD CAENIRLLLP HVKPVSERPE WFAQ INDWK ARFPFSLYEK QSPEGPIKPQ ALIEKLSDLT APIKDRTIIT TGVGQHQMWA AQHFRWRHPR TMITSGGLGT MGYGL PAAI GAKVARPDCL VIDIDGDASF NMTLTELTTA AQFNIGVKVL LLNNEEQGMV TQWQNLFYED RYSHTHQKNP DFVPMA RSM GVAAERCTKP SEVEEKLKWL IESDGPALLE VFTDRKVPVL PMVPAGSALH EFLVYDEAKE KERKALLRSR TAPEYLH K

UniProtKB: Acetolactate synthase

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Macromolecule #2: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 2 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #3: THIAMINE DIPHOSPHATE

MacromoleculeName: THIAMINE DIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 2 / Formula: TPP
Molecular weightTheoretical: 425.314 Da
Chemical component information

ChemComp-TPP:
THIAMINE DIPHOSPHATE

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Macromolecule #4: FLAVIN-ADENINE DINUCLEOTIDE

MacromoleculeName: FLAVIN-ADENINE DINUCLEOTIDE / type: ligand / ID: 4 / Number of copies: 2 / Formula: FAD
Molecular weightTheoretical: 785.55 Da
Chemical component information

ChemComp-FAD:
FLAVIN-ADENINE DINUCLEOTIDE / FAD*YM

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Macromolecule #5: (1R,2R,4aR,8R,8aR)-8-[(3S,5R)-5-(3-hydroxypropyl)-2,4-dioxopyrrol...

MacromoleculeName: (1R,2R,4aR,8R,8aR)-8-[(3S,5R)-5-(3-hydroxypropyl)-2,4-dioxopyrrolidin-3-yl]-3,8-dimethyl-2-propyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carbaldehyde
type: ligand / ID: 5 / Number of copies: 2 / Formula: A1CXH
Molecular weightTheoretical: 389.528 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 65.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5ims

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.36 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 125472
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: MAXIMUM LIKELIHOOD

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