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- PDB-8g6f: Structure of the Plasmodium falciparum 20S proteasome beta-6 A117... -

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Basic information

Entry
Database: PDB / ID: 8g6f
TitleStructure of the Plasmodium falciparum 20S proteasome beta-6 A117D mutant complexed with inhibitor WLW-vs
Components
  • (Proteasome subunit alpha type- ...) x 7
  • (Proteasome subunit beta- ...) x 6
  • Proteasome endopeptidase complex
KeywordsHYDROLASE/HYDROLASE INHIBITOR / beta-6 A117D / inhibitor / proteasome / HYDROLASE / HYDROLASE-HYDROLASE 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 / KEAP1-NFE2L2 pathway / UCH proteinases / Ub-specific processing proteases / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation / Neutrophil degranulation ...Cross-presentation of soluble exogenous antigens (endosomes) / : / Orc1 removal from chromatin / CDK-mediated phosphorylation and removal of Cdc6 / KEAP1-NFE2L2 pathway / UCH proteinases / Ub-specific processing proteases / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation / Neutrophil degranulation / proteasome core complex / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteolysis involved in protein catabolic process / proteasomal protein catabolic process / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / nucleus / cytosol / cytoplasm
Similarity search - Function
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 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
Chem-7F1 / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome endopeptidase complex / Proteasome subunit beta / Proteasome subunit alpha type-2, putative / Proteasome subunit alpha type-3, putative / Proteasome subunit beta / Proteasome subunit beta / Proteasome subunit alpha type-6, putative ...Chem-7F1 / Proteasome subunit alpha type / Proteasome subunit beta / Proteasome endopeptidase complex / Proteasome subunit beta / Proteasome subunit alpha type-2, putative / Proteasome subunit alpha type-3, 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-1, putative / Proteasome subunit beta
Similarity search - Component
Biological speciesPlasmodium falciparum Dd2 (eukaryote)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.58 Å
AuthorsHsu, H.-C. / Li, H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI143714 United States
CitationJournal: Nat Commun / Year: 2023
Title: Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors.
Authors: Hao-Chi Hsu / Daqiang Li / Wenhu Zhan / Jianxiang Ye / Yi Jing Liu / Annie Leung / Junling Qin / Benigno Crespo / Francisco-Javier Gamo / Hao Zhang / Liwang Cui / Alison Roth / Laura A ...Authors: Hao-Chi Hsu / Daqiang Li / Wenhu Zhan / Jianxiang Ye / Yi Jing Liu / Annie Leung / Junling Qin / Benigno Crespo / Francisco-Javier Gamo / Hao Zhang / Liwang Cui / Alison Roth / Laura A Kirkman / Huilin Li / Gang Lin /
Abstract: The proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with ...The proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with artemisinins. We recently developed a macrocyclic peptide, TDI-8304, that is highly selective for Pf20S over human proteasomes and is potent in vitro and in vivo against P. falciparum. A mutation in the Pf20S β6 subunit, A117D, confers resistance to TDI-8304, yet enhances both enzyme inhibition and anti-parasite activity of a tripeptide vinyl sulfone β2 inhibitor, WLW-vs. Here we present the high-resolution cryo-EM structures of Pf20S with TDI-8304, of human constitutive proteasome with TDI-8304, and of Pf20Sβ6 with WLW-vs that give insights into the species selectivity of TDI-8304, resistance to it, and the collateral sensitivity associated with resistance, including that TDI-8304 binds β2 and β5 in wild type Pf20S as well as WLW-vs binds β2 and β5 in Pf20Sβ6. We further show that TDI-8304 kills P. falciparum as quickly as chloroquine and artemisinin and is active against P. cynomolgi at the liver stage. This increases interest in using these structures to facilitate the development of Pf20S inhibitors that target multiple proteasome subunits and limit the emergence of resistance.
History
DepositionFeb 15, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 20, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 3, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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-3
D: Proteasome subunit alpha type-4
E: Proteasome subunit alpha type-5
F: Proteasome subunit alpha type-1
G: Proteasome subunit alpha type-3
H: Proteasome endopeptidase complex
I: Proteasome subunit beta-2
J: Proteasome subunit beta-3
K: Proteasome subunit beta-4
L: Proteasome subunit beta-5
M: Proteasome subunit beta-6
N: Proteasome subunit beta-7
O: Proteasome subunit alpha type-6
P: Proteasome subunit alpha type-2
Q: Proteasome subunit alpha type-3
R: Proteasome subunit alpha type-4
S: Proteasome subunit alpha type-5
T: Proteasome subunit alpha type-1
U: Proteasome subunit alpha type-3
V: Proteasome endopeptidase complex
W: Proteasome subunit beta-2
X: Proteasome subunit beta-3
Y: Proteasome subunit beta-4
Z: Proteasome subunit beta-5
a: Proteasome subunit beta-6
b: Proteasome subunit beta-7
hetero molecules


Theoretical massNumber of molelcules
Total (without water)765,74232
Polymers762,97828
Non-polymers2,7634
Water10,791599
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Proteasome subunit alpha type- ... , 7 types, 14 molecules AOBPCQDRESFTGU

#1: Protein Proteasome subunit alpha type-6 /


Mass: 29531.656 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote)
References: UniProt: Q8IAR3, proteasome endopeptidase complex
#2: Protein Proteasome subunit alpha type-2 /


Mass: 26556.391 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: C6KST3
#3: Protein Proteasome subunit alpha type-3 /


Mass: 27977.664 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: Q8IDG3
#4: Protein Proteasome subunit alpha type-4 /


Mass: 27263.285 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: Q8IDG2
#5: Protein Proteasome subunit alpha type-5 /


Mass: 28417.367 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: A0A0L7LVZ5
#6: Protein Proteasome subunit alpha type-1 /


Mass: 28871.697 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: Q8IK90
#7: Protein Proteasome subunit alpha type-3 /


Mass: 29324.295 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote)
References: UniProt: O77396, proteasome endopeptidase complex

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Protein , 1 types, 2 molecules HV

#8: Protein Proteasome endopeptidase complex /


Mass: 29143.936 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: A0A0L7M1M6

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Proteasome subunit beta- ... , 6 types, 12 molecules IWJXKYLZMaNb

#9: Protein Proteasome subunit beta-2 /


Mass: 25104.885 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: Q8I6T3
#10: Protein Proteasome subunit beta-3 /


Mass: 24533.131 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: Q8I261
#11: Protein Proteasome subunit beta-4 /


Mass: 22889.105 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: Q8IKC9
#12: Protein Proteasome subunit beta-5 /


Mass: 23620.646 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: Q8IJT1
#13: Protein Proteasome subunit beta-6 /


Mass: 27345.213 Da / Num. of mol.: 2 / Mutation: A117D / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: A0A2I0BU46
#14: Protein Proteasome subunit beta-7 /


Mass: 30909.893 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum Dd2 (eukaryote) / References: UniProt: A0A0L7LW03

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Non-polymers , 2 types, 603 molecules

#15: Chemical
ChemComp-7F1 / (2S)-N-[(E,2S)-1-(1H-indol-3-yl)-4-methylsulfonyl-but-3-en-2-yl]-2-[[(2S)-3-(1H-indol-3-yl)-2-(2-morpholin-4-ylethanoylamino)propanoyl]amino]-4-methyl-pentanamide


Mass: 690.852 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C36H46N6O6S / Feature type: SUBJECT OF INVESTIGATION
#16: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 599 / Source method: isolated from a natural source / Formula: H2O

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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: the Plasmodium falciparum 20S proteasome beta-6 A117D mutant complexed with inhibitor WLW-vs
Type: COMPLEX / Entity ID: #1-#14 / Source: NATURAL
Molecular weightValue: 0.7 MDa / Experimental value: YES
Source (natural)Organism: Plasmodium falciparum Dd2 (eukaryote)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMTris1
2100 mMKClKCl1
35 mMMgCl2MgCl21
41 mMDTT1
52 %DMF1
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: partially purified
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 105000 X / Nominal defocus max: 1800 nm / Nominal defocus min: 1300 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: 1.3 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 24806
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV
Image scansWidth: 11520 / Height: 8184

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Processing

EM software
IDNameVersionCategory
1cryoSPARC3.3.2particle selection
2SerialEM4image acquisition
4CTFFIND4CTF correction
7UCSF Chimera1.14model fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARC3.3.2classification
12cryoSPARC3.3.23D reconstruction
19PHENIX1.20.1-4487model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 337322
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.58 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 74883 / Algorithm: BACK PROJECTION / Num. of class averages: 3 / Symmetry type: POINT
Atomic model buildingB value: 43.89 / Protocol: RIGID BODY FIT / Space: REAL
Atomic model buildingPDB-ID: 8G6E

8g6e


Accession code: 8G6E / Source name: PDB / Type: experimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00353013
ELECTRON MICROSCOPYf_angle_d0.4671611
ELECTRON MICROSCOPYf_dihedral_angle_d5.3477164
ELECTRON MICROSCOPYf_chiral_restr0.0427982
ELECTRON MICROSCOPYf_plane_restr0.0039130

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