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Yorodumi- PDB-8g6f: Structure of the Plasmodium falciparum 20S proteasome beta-6 A117... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8g6f | ||||||
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Title | Structure of the Plasmodium falciparum 20S proteasome beta-6 A117D mutant complexed with inhibitor WLW-vs | ||||||
Components |
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Keywords | HYDROLASE/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 | ||||||
Biological species | Plasmodium falciparum Dd2 (eukaryote) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.58 Å | ||||||
Authors | Hsu, H.-C. / Li, H. | ||||||
Funding support | United States, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8g6f.cif.gz | 1.2 MB | Display | PDBx/mmCIF format |
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PDB format | pdb8g6f.ent.gz | 1 MB | Display | PDB format |
PDBx/mmJSON format | 8g6f.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/g6/8g6f ftp://data.pdbj.org/pub/pdb/validation_reports/g6/8g6f | HTTPS FTP |
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-Related structure data
Related structure data | 29765MC 8g6eC 8ud9C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Proteasome subunit alpha type- ... , 7 types, 14 molecules AOBPCQDRESFTGU
#1: Protein | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 / ( #16: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: the Plasmodium falciparum 20S proteasome beta-6 A117D mutant complexed with inhibitor WLW-vs Type: COMPLEX / Entity ID: #1-#14 / Source: NATURAL | ||||||||||||||||||||||||||||||
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Molecular weight | Value: 0.7 MDa / Experimental value: YES | ||||||||||||||||||||||||||||||
Source (natural) | Organism: Plasmodium falciparum Dd2 (eukaryote) | ||||||||||||||||||||||||||||||
Buffer solution | pH: 7.5 | ||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: partially purified | ||||||||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 | ||||||||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 279 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: 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 holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average 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 optics | Energyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV |
Image scans | Width: 11520 / Height: 8184 |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 337322 | ||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 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 building | B value: 43.89 / Protocol: RIGID BODY FIT / Space: REAL | ||||||||||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 8G6E Accession code: 8G6E / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||||||||||||||||||
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