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- PDB-9o3e: Plasmodium falciparum 20S proteasome bound to inhibitor 159 -

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Basic information

Entry
Database: PDB / ID: 9o3e
TitlePlasmodium falciparum 20S proteasome bound to inhibitor 159
Components
  • (Proteasome endopeptidase ...) x 3
  • (Proteasome subunit ...) x 11
KeywordsCYTOSOLIC PROTEIN / Malaria / Plasmodium falciparum / proteasome / drug discovery / CYTOSOLIC PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


ER-Phagosome pathway / Cross-presentation of soluble exogenous antigens (endosomes) / Antigen processing: Ub, ATP-independent proteasomal degradation / Proteasome assembly / Orc1 removal from chromatin / CDK-mediated phosphorylation and removal of Cdc6 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / KEAP1-NFE2L2 pathway / UCH proteinases / Ub-specific processing proteases ...ER-Phagosome pathway / Cross-presentation of soluble exogenous antigens (endosomes) / Antigen processing: Ub, ATP-independent proteasomal degradation / Proteasome assembly / Orc1 removal from chromatin / CDK-mediated phosphorylation and removal of Cdc6 / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / KEAP1-NFE2L2 pathway / UCH proteinases / Ub-specific processing proteases / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation / MAPK6/MAPK4 signaling / ABC-family proteins mediated transport / AUF1 (hnRNP D0) binds and destabilizes mRNA / Neutrophil degranulation / proteasome core complex / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / threonine-type endopeptidase activity / proteasome core complex, alpha-subunit complex / ubiquitin-dependent protein catabolic process / endopeptidase activity / proteasome-mediated ubiquitin-dependent protein catabolic process / hydrolase activity / nucleus / cytoplasm / cytosol
Similarity search - Function
Proteasome subunit alpha 1 / 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 subunit alpha 1 / 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 beta / Proteasome subunit alpha type-2 / Proteasome subunit alpha type-3, putative / Proteasome subunit beta type-6, putative / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit alpha type-6, putative / Proteasome subunit alpha type / Proteasome subunit alpha type ...: / Proteasome subunit beta / Proteasome subunit alpha type-2 / Proteasome subunit alpha type-3, putative / Proteasome subunit beta type-6, putative / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit alpha type-6, putative / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome subunit alpha type-1, putative / Proteasome subunit beta
Similarity search - Component
Biological speciesPlasmodium falciparum 3D7 (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.79 Å
AuthorsHan, Y. / Deng, X. / Ray, S. / Phillips, M.
Funding support United States, 4items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI103947 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI155784 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM007062 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RP220582 United States
CitationJournal: J Med Chem / Year: 2025
Title: Optimization of Species-Selective Reversible Proteasome Inhibitors for the Treatment of Malaria.
Authors: Suraksha Gahalawat / Sneha Ray / Xiaoyu Zhang / Xiaoyi Deng / Yan Han / Zhe Chen / Aloysus Lawong / David M Shackleford / Kasiram Katneni / Gong Chen / Peng Li / Alice Ng / Longjin Zhong / ...Authors: Suraksha Gahalawat / Sneha Ray / Xiaoyu Zhang / Xiaoyi Deng / Yan Han / Zhe Chen / Aloysus Lawong / David M Shackleford / Kasiram Katneni / Gong Chen / Peng Li / Alice Ng / Longjin Zhong / Meiyu Hu / Mitchell McInerney / Wen Wang / Jessica Saunders / Daniel Collins / Jaya Jayaseelan / Cassandra L Noack / Bikash C Maity / Nirupam De / Benoît Laleu / Simon F Campbell / Margaret A Phillips / Susan A Charman / Joseph M Ready /
Abstract: Malaria remains a critical global health challenge, with increasing resistance to frontline therapies necessitating novel drug targets. The proteasome has emerged as a promising target for ...Malaria remains a critical global health challenge, with increasing resistance to frontline therapies necessitating novel drug targets. The proteasome has emerged as a promising target for antimalarial drug discovery. This study describes efforts to optimize a series of species-selective reversible inhibitors targeting the 20S proteasome. Starting from the carboxypiperidine scaffold identified through a high-throughput viability screen, we conducted iterative structure-activity relationship studies, leading to the development of highly potent and selective inhibitors with good oral bioavailability. Lead compounds demonstrated nanomolar potency against blood-stage parasites and selective inhibition of the parasite proteasome over the human counterpart. Cryo-EM structural studies confirmed binding at the β5 subunit, while in vivo pharmacokinetic studies identified promising candidates for further development. These findings support proteasome inhibition as a viable strategy for novel antimalarial drug development.
History
DepositionApr 7, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)768,23630
Polymers767,38128
Non-polymers8552
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 endopeptidase ... , 3 types, 6 molecules AOBPFT

#1: Protein Proteasome endopeptidase complex


Mass: 29531.656 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: Q8IAR3, proteasome endopeptidase complex
#2: Protein Proteasome endopeptidase complex


Mass: 26556.391 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: C6KST3, proteasome endopeptidase complex
#6: Protein Proteasome endopeptidase complex


Mass: 28871.697 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: Q8IK90, proteasome endopeptidase complex

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Proteasome subunit ... , 11 types, 22 molecules CQDRESGUHVJXKYLZNbWIMa

#3: Protein Proteasome subunit alpha type


Mass: 27977.664 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: Q8IDG3, proteasome endopeptidase complex
#4: Protein Proteasome subunit alpha type


Mass: 27263.285 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: Q8IDG2, proteasome endopeptidase complex
#5: Protein Proteasome subunit alpha type


Mass: 28417.367 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: Q8IBI3, proteasome endopeptidase complex
#7: Protein Proteasome subunit alpha type-3, putative


Mass: 29324.295 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: O77396, proteasome endopeptidase complex
#8: Protein Proteasome subunit beta type-6, putative


Mass: 29143.936 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: Q8I0U7, proteasome endopeptidase complex
#9: Protein Proteasome subunit beta


Mass: 24533.131 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: Q8I261, proteasome endopeptidase complex
#10: Protein Proteasome subunit beta


Mass: 22889.105 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: Q8IKC9, proteasome endopeptidase complex
#11: Protein Proteasome subunit beta type


Mass: 23620.646 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: Q8IJT1, proteasome endopeptidase complex
#12: Protein Proteasome subunit beta


Mass: 33155.211 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
#13: Protein Proteasome subunit beta


Mass: 25104.885 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: Q8I6T3, proteasome endopeptidase complex
#14: Protein Proteasome subunit beta


Mass: 27301.203 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote)
References: UniProt: A0A5K1K7U1, proteasome endopeptidase complex

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Non-polymers , 1 types, 2 molecules

#15: Chemical ChemComp-A1B74 / (3S)-N~3~-{(1S)-1-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]ethyl}-N~1~-ethoxypiperidine-1,3-dicarboxamide


Mass: 427.520 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H25N5O3S / 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: Plasmodium falciparum 20S proteasome bound with inhibitor 159
Type: COMPLEX / Entity ID: #1-#14 / Source: NATURAL
Molecular weightValue: 0.75 MDa / Experimental value: NO
Source (natural)Organism: Plasmodium falciparum 3D7 (eukaryote)
Buffer solutionpH: 7.6
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTrisC4H11NO31
2150 mMsodium chlorideNaCl1
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 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: 2400 nm / Nominal defocus min: 900 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)
EM imaging opticsEnergyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.3.1particle selection
2SerialEMimage acquisition
4cryoSPARC4.3.1CTF correction
9cryoSPARC4.3.1initial Euler assignment
10cryoSPARC4.3.1final Euler assignment
11cryoSPARC4.3.1classification
12cryoSPARC4.3.13D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 347716
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.79 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 45233 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model buildingPDB-ID: 7LXT

7lxt


Accession code: 7LXT / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.79 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00449479
ELECTRON MICROSCOPYf_angle_d0.69966781
ELECTRON MICROSCOPYf_dihedral_angle_d6.0696650
ELECTRON MICROSCOPYf_chiral_restr0.0477520
ELECTRON MICROSCOPYf_plane_restr0.0048471

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