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Yorodumi- PDB-8g6e: Structure of the Plasmodium falciparum 20S proteasome complexed w... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8g6e | ||||||
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Title | Structure of the Plasmodium falciparum 20S proteasome complexed with inhibitor TDI-8304 | ||||||
Components | (Proteasome subunit ...) x 14 | ||||||
Keywords | HYDROLASE/HYDROLASE INHIBITOR / proteasome / inhibitor / 20S / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex | ||||||
Function / homology | Function and homology information proteasome core complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / proteasomal protein catabolic process / threonine-type endopeptidase activity / proteolysis involved in protein catabolic process / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / nucleus / cytoplasm Similarity search - Function | ||||||
Biological species | Plasmodium falciparum NF54 (eukaryote) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.18 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 | 8g6e.cif.gz | 1.2 MB | Display | PDBx/mmCIF format |
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PDB format | pdb8g6e.ent.gz | 1 MB | Display | PDB format |
PDBx/mmJSON format | 8g6e.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8g6e_validation.pdf.gz | 2.1 MB | Display | wwPDB validaton report |
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Full document | 8g6e_full_validation.pdf.gz | 2.1 MB | Display | |
Data in XML | 8g6e_validation.xml.gz | 153.4 KB | Display | |
Data in CIF | 8g6e_validation.cif.gz | 248.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/g6/8g6e ftp://data.pdbj.org/pub/pdb/validation_reports/g6/8g6e | HTTPS FTP |
-Related structure data
Related structure data | 29764MC 8g6fC 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 ... , 14 types, 28 molecules AOBPCQDRESFTGUHVIWJXKYLZMaNb
#1: Protein | Mass: 29531.656 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: W7JVP8 #2: Protein | Mass: 26556.391 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: A0A2I0BQ13 #3: Protein | Mass: 27977.664 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: W7KN95 #4: Protein | Mass: 27263.285 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: A0A2I0BS43 #5: Protein | Mass: 28417.367 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: A0A2I0BP34 #6: Protein | Mass: 28742.584 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: W7K5W7 #7: Protein | Mass: 29324.295 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: W7K040 #8: Protein | Mass: 29143.936 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: W7JUG8 #9: Protein | Mass: 25104.885 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: W7K1J4 #10: Protein | Mass: 24533.131 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: A0A2I0BXS0 #11: Protein | Mass: 22889.105 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: W7JKG5 #12: Protein | Mass: 23620.646 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (eukaryote) / References: UniProt: W7K6A8 #13: Protein | Mass: 27301.203 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Plasmodium falciparum NF54 (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 NF54 (eukaryote) / References: UniProt: W7K6I2 |
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-Non-polymers , 2 types, 224 molecules
#15: Chemical | ChemComp-YRE / ( #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: Plasmodium falciparum 20S proteasome complexed with inhibitor TDI-8304 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 NF54 (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 | ||||||||||||||||||||||||||||||
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 FIELD / 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: 1.5 sec. / Electron dose: 66 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 29343 |
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: 657066 | ||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 2.18 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 305581 / Algorithm: BACK PROJECTION / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||
Atomic model building | B value: 21.44 / Protocol: RIGID BODY FIT / Space: REAL | ||||||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 6MUW Accession code: 6MUW / Source name: PDB / Type: experimental model | ||||||||||||||||||||||||||||||||||||
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