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- PDB-9yk0: cryoEM structure of Aspergillus fumigatus acetolactate synthase (... -

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Basic information

Entry
Database: PDB / ID: 9yk0
TitlecryoEM structure of Aspergillus fumigatus acetolactate synthase (ALS) in complex with a novel inhibitor
ComponentsAcetolactate synthase
KeywordsPLANT PROTEIN / antifungal target / herbicide target / anti fugal infection / natural product
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
: / FLAVIN-ADENINE DINUCLEOTIDE / THIAMINE DIPHOSPHATE / Acetolactate synthase
Similarity search - Component
Biological speciesAspergillus fumigatus (mold)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.36 Å
AuthorsHu, Y.
Funding support1items
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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2026Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 18, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Acetolactate synthase
B: Acetolactate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,86510
Polymers140,6162
Non-polymers3,2498
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Acetolactate synthase


Mass: 70307.812 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Aspergillus fumigatus (mold) / Gene: AFUB_038840 / Production host: Escherichia coli (E. coli) / References: UniProt: B0XXW9, acetolactate synthase
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-TPP / THIAMINE DIPHOSPHATE


Mass: 425.314 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H19N4O7P2S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: FAD*YM
#5: Chemical ChemComp-A1CXH / (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


Mass: 389.528 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H35NO4 / Feature type: SUBJECT OF INVESTIGATION
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: Aspergillus fumigatus Acetolactate synthase / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.133 MDa / Experimental value: NO
Source (natural)Organism: Aspergillus fumigatus (mold)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
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: 2400 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 65 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 125472 / Symmetry type: POINT
RefinementHighest resolution: 2.36 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029304
ELECTRON MICROSCOPYf_angle_d0.59612650
ELECTRON MICROSCOPYf_dihedral_angle_d5.7681366
ELECTRON MICROSCOPYf_chiral_restr0.0541400
ELECTRON MICROSCOPYf_plane_restr0.0051626

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