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- PDB-8w2f: Plasmodium falciparum 20S proteasome bound to an inhibitor -

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Basic information

Entry
Database: PDB / ID: 8w2f
TitlePlasmodium falciparum 20S proteasome bound to an inhibitor
Components
  • (Proteasome endopeptidase ...) x 3
  • (Proteasome subunit ...) x 11
KeywordsCYTOSOLIC PROTEIN/INHIBITOR / Malaria / Plasmodium falciparum / proteasome / drug discovery / CYTOSOLIC PROTEIN / CYTOSOLIC PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


Cross-presentation of soluble exogenous antigens (endosomes) / 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 / MAPK6/MAPK4 signaling / Antigen processing: Ubiquitination & Proteasome degradation ...Cross-presentation of soluble exogenous antigens (endosomes) / 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 / MAPK6/MAPK4 signaling / Antigen processing: Ubiquitination & Proteasome degradation / 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 / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / threonine-type endopeptidase activity / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / hydrolase activity / nucleus / cytoplasm / cytosol
Similarity search - Function
Proteasome subunit beta 1 / Proteasome subunit alpha 1 / : / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha6 / Proteasome subunit alpha5 / Proteasome beta-type subunits signature. / Peptidase T1A, proteasome beta-subunit ...Proteasome subunit beta 1 / Proteasome subunit alpha 1 / : / Proteasome subunit beta 4 / Proteasome subunit beta 2 / Proteasome beta 3 subunit / Proteasome subunit alpha6 / Proteasome subunit alpha5 / 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 alpha-type subunit / Proteasome alpha-type subunit profile. / Proteasome B-type subunit / Proteasome beta-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, putative / Proteasome subunit alpha type-3, putative / Proteasome subunit beta / Proteasome subunit beta type-6, putative / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit alpha type-6, putative / Proteasome subunit alpha type ...: / Proteasome subunit beta / Proteasome subunit alpha type-2, putative / Proteasome subunit alpha type-3, putative / Proteasome subunit beta / 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: 3.1 Å
AuthorsHan, Y. / Deng, X. / Ray, S. / Chen, Z. / 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: Cell Chem Biol / Year: 2024
Title: Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria
Authors: Lawong, A. / Gahalawat, S.
History
DepositionFeb 20, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2024Provider: 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
I: Proteasome subunit beta
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
X: Proteasome subunit beta
Y: Proteasome subunit beta
Z: Proteasome subunit beta type
M: Proteasome subunit beta
a: Proteasome subunit beta
W: Proteasome subunit beta
b: Proteasome subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)767,15330
Polymers766,31228
Non-polymers8412
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 CQDRESGUHVIWJXKYLZNbMa

#3: Protein Proteasome subunit alpha type


Mass: 27443.037 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum 3D7 (eukaryote) / References: UniProt: Q8IDG3
#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: 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
#10: 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
#11: 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
#12: 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
#13: Protein Proteasome subunit beta


Mass: 33155.211 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: tag was introduced using the CRISPR/Cas9 system at the endogenous locus
Source: (gene. exp.) Plasmodium falciparum 3D7 (eukaryote) / Gene: PF3D7_0803800 / Production host: Plasmodium falciparum 3D7 (eukaryote) / References: UniProt: Q7K6A9
#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-A1AE6 / (3S)-1-[(2-fluoroethoxy)acetyl]-N-{[(4P)-4-(6-methylpyridin-3-yl)-1,3-thiazol-2-yl]methyl}piperidine-3-carboxamide


Mass: 420.501 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H25FN4O3S / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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 an inhibitor
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.: 1.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / 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: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN 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: 2200 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 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
1Gautomatch0.56particle selection
2SerialEMimage acquisition
4GctfCTF correction
9RELION4.0.1initial Euler assignment
10RELION4.0.1final Euler assignment
11RELION4.0.1classification
12RELION4.0.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1074710
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 20317 / Algorithm: BACK PROJECTION / Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model buildingPDB-ID: 5FMG

5fmg


Accession code: 5FMG / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00349882
ELECTRON MICROSCOPYf_angle_d0.5167328
ELECTRON MICROSCOPYf_dihedral_angle_d5.476712
ELECTRON MICROSCOPYf_chiral_restr0.0437576
ELECTRON MICROSCOPYf_plane_restr0.0048547

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