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- PDB-9q6f: Structure of Plasmodium falciparum 20S proteasome bound to an asp... -

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Basic information

Entry
Database: PDB / ID: 9q6f
TitleStructure of Plasmodium falciparum 20S proteasome bound to an asparagine-ethylenediamine based inhibitor TDI6245
Components(Proteasome subunit ...) x 14
KeywordsHYDROLASE / Plasmodium falciparum antimalarial proteasome inhibitors
Function / homology
Function and homology information


proteasome core complex / : / proteasome core complex, beta-subunit complex / threonine-type endopeptidase activity / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / peptidase activity / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / nucleus / cytoplasm
Similarity search - Function
Proteasome subunit alpha 1 / : / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha5 / Proteasome subunit alpha6 / Proteasome beta-type subunits signature. / Peptidase T1A, proteasome beta-subunit / Proteasome beta-type subunit, conserved site ...Proteasome subunit alpha 1 / : / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha5 / Proteasome subunit alpha6 / Proteasome beta-type subunits signature. / Peptidase T1A, proteasome beta-subunit / Proteasome beta-type subunit, conserved site / Proteasome subunit A N-terminal signature / Proteasome alpha-type subunits signature. / Proteasome alpha-subunit, N-terminal domain / Proteasome subunit A N-terminal signature Add an annotation / Proteasome B-type subunit / Proteasome beta-type subunit profile. / Proteasome alpha-type subunit / Proteasome alpha-type subunit profile. / Proteasome subunit / Proteasome, subunit alpha/beta / Nucleophile aminohydrolases, N-terminal
Similarity search - Domain/homology
: / Proteasome subunit alpha type / Proteasome subunit alpha type-2 / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Uncharacterized protein / Proteasome alpha-type subunits domain-containing protein / Proteasome alpha-type subunits domain-containing protein ...: / Proteasome subunit alpha type / Proteasome subunit alpha type-2 / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit beta / Uncharacterized protein / Proteasome alpha-type subunits domain-containing protein / Proteasome alpha-type subunits domain-containing protein / Proteasome subunit beta / Proteasome alpha-type subunits domain-containing protein / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit alpha type
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.86 Å
AuthorsHsu, H.C. / Li, H.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R21AI123794 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI143714 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI177635 United States
CitationJournal: ACS Omega / Year: 2026
Title: Structure-Activity Relationship Study of Antimalarial Asparagine-Derived Proteasome Inhibitors.
Authors: Hao Zhang / Daqiang Li / Hao-Chi Hsu / Akshay Vishwanatha / Wenhu Zhan / Takafumi Yukawa / Joseph Visone / Toshihiro Imaeda / Rei Okamoto / Pavla Fajtova / Ryoma Hara / Masanori Kawasaki / ...Authors: Hao Zhang / Daqiang Li / Hao-Chi Hsu / Akshay Vishwanatha / Wenhu Zhan / Takafumi Yukawa / Joseph Visone / Toshihiro Imaeda / Rei Okamoto / Pavla Fajtova / Ryoma Hara / Masanori Kawasaki / Kenjiro Sato / Mayako Michino / Shreeya Garg / Oriana Kreutzfeld / Patrick K Tumwebaze / Stephen Orena / Martin Okitwi / Kazuyoshi Aso / Roland A Cooper / Philip J Rosenthal / Peter T Meinke / Michael Foley / Anthony J O'Donoghue / Huilin Li / Laura A Kirkman / Gang Lin /
Abstract: Malaria remains a significant global health threat, affecting millions of lives each year. The causative agents, parasites, are highly resilient and have developed resistance to nearly all existing ...Malaria remains a significant global health threat, affecting millions of lives each year. The causative agents, parasites, are highly resilient and have developed resistance to nearly all existing antimalarial drugs. The 20S proteasome core (20S), a central component of the parasite's proteostasis pathway, has emerged as a promising therapeutic target. Inhibiting 20S effectively suppresses parasite growth at multiple stages of the parasite life cycle, synergizes with artemisinin-based therapies, and shows no cross-resistance with other antimalarial drug classes. Previously, we identified a novel class of proteasome inhibitors with potent activity against 20S, which we subsequently optimized for improved potency and selectivity over human proteasomes. However, these inhibitors exhibited suboptimal pharmacokinetic properties, potentially attributable to a high number of rotatable bonds and hydrogen bond donors. Here, we describe further optimization of this inhibitor class and provide structural insights into 20S-inhibitor interactions. Cryo-EM structural studies reveal a novel binding pose of the inhibitor at the 20S β5 active site, explaining the enhanced activity of an -cap sulfonamide modification compared to an -cap amide. These findings offer insights into the development of next-generation antimalarial 20S-targeting compounds with improved drug-like properties.
History
DepositionAug 22, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 29, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.1Aug 19, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Proteasome subunit alpha type-6
B: Proteasome subunit alpha type-2
C: Proteasome subunit alpha type
D: Proteasome subunit alpha type
E: Proteasome subunit alpha type
F: Proteasome subunit alpha type-1
G: Proteasome subunit alpha type-3
H: Proteasome subunit beta type-6
I: Proteasome subunit beta
J: Proteasome subunit beta
K: Proteasome subunit beta
L: Proteasome subunit beta
M: Proteasome subunit beta
N: Proteasome subunit beta
O: Proteasome subunit alpha type-6
P: Proteasome subunit alpha type-2
Q: Proteasome subunit alpha type
R: Proteasome subunit alpha type
S: Proteasome subunit alpha type
T: Proteasome subunit alpha type-1
U: Proteasome subunit alpha type-3
V: Proteasome subunit beta type-6
W: Proteasome subunit beta
X: Proteasome subunit beta
Y: Proteasome subunit beta
Z: Proteasome subunit beta
a: Proteasome subunit beta
b: Proteasome subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)771,45930
Polymers770,45828
Non-polymers1,0012
Water00
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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Proteasome subunit ... , 14 types, 28 molecules AOBPCQDRESFTGUHVIWJXKYLZMaNb

#1: Protein Proteasome subunit alpha type-6


Mass: 29531.656 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_2446, CYL21_1296, PFNF54_02078 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: W7JVP8
#2: Protein Proteasome subunit alpha type-2


Mass: 26556.391 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_4966, CYL21_4378 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A2I0BQ13
#3: Protein Proteasome subunit alpha type


Mass: 27977.664 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_4303, CYL21_5399, PFNF54_00272 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: W7KN95
#4: Protein Proteasome subunit alpha type


Mass: 27263.285 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_4499, CYL21_5482 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A2I0BS43
#5: Protein Proteasome subunit alpha type


Mass: 28417.367 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_5367, CYL21_5183 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A2I0BP34
#6: Protein Proteasome subunit alpha type-1


Mass: 28742.584 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_0007, CYL21_2454, PFNF54_05872 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: W7K5W7
#7: Protein Proteasome subunit alpha type-3


Mass: 29324.295 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_3814, CYL21_3097, PFNF54_00518 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: W7K040
#8: Protein Proteasome subunit beta type-6


Mass: 29143.936 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_4201, CYL21_1069, PFNF54_02629 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: W7JUG8
#9: Protein Proteasome subunit beta


Mass: 25104.885 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_2690, CYL21_4000, PFNF54_04378 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: W7K1J4
#10: Protein Proteasome subunit beta


Mass: 24533.131 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_2185, CYL21_3554 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A2I0BXS0
#11: Protein Proteasome subunit beta


Mass: 22889.105 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_0043, CYL21_2079, PFNF54_05825 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: W7JKG5
#12: Protein Proteasome subunit beta


Mass: 23620.646 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_4752, CYL21_3663, PFNF54_02809 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: W7K6A8
#13: Protein Proteasome subunit beta


Mass: 27301.203 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_3362, CYL21_3125 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: A0A2I0BU46
#14: Protein Proteasome subunit beta


Mass: 34822.988 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Gene: CK202_2268, CYL21_1305, PFNF54_02044 / Plasmid: pACEBac1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: W7K6I2

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Non-polymers , 1 types, 2 molecules

#15: Chemical ChemComp-A1CRS / N~4~-tert-butyl-N~2~-(4-methylbenzene-1-sulfonyl)-N~1~-[2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-L-aspartamide


Mass: 500.610 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H32N4O5S / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationN

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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: Complex of Plasmodium falciparum 20S with inhibitor TDI-6245
Type: COMPLEX
Details: recombinant Plasmodium falciparum 20S complexed with inhibitor TDI-6245
Entity ID: #1-#14 / Source: RECOMBINANT
Molecular weightValue: 0.7 MDa / Experimental value: NO
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Cell: Sf9 / Plasmid: pACEBac1
Buffer solutionpH: 7.5 / Details: 20 mM Tris, pH 7.5, 5 mM MgCl2, and 100 mM KCl
SpecimenConc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 279 K

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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 magnification: 105000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 1.2 sec. / Electron dose: 58 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 24167
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV
Image scansWidth: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.4particle selection
2SerialEM4image acquisition
7UCSF Chimera1.17model fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC4.43D reconstruction
13PHENIX1.20.1_4487model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 17354694
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.86 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 124807 / Algorithm: BACK PROJECTION / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model buildingPDB-ID: 8G6E

8g6e


Accession code: 8G6E / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.86 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00251774
ELECTRON MICROSCOPYf_angle_d0.42469916
ELECTRON MICROSCOPYf_dihedral_angle_d4.8976984
ELECTRON MICROSCOPYf_chiral_restr0.0417814
ELECTRON MICROSCOPYf_plane_restr0.0028916

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