[English] 日本語
Yorodumi- EMDB-23574: Structure of Plasmodium falciparum 20S proteasome with bound bort... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-23574 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Structure of Plasmodium falciparum 20S proteasome with bound bortezomib | |||||||||
Map data | Main EM map used for refinement | |||||||||
Sample |
| |||||||||
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 / proteasomal protein catabolic process / proteasome core complex, alpha-subunit complex / 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 | |||||||||
Biological species | Plasmodium falciparum 3D7 (eukaryote) / Plasmodium falciparum (isolate 3D7) (eukaryote) / Plasmodium falciparum (malaria parasite P. falciparum) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||
Authors | Liu B / Hanssen E / Leis AP / Xie SC / Morton CJ / Metcalfe RD / Tilley L / Griffin MDW | |||||||||
Funding support | United States, Australia, 2 items
| |||||||||
Citation | Journal: Proc Natl Acad Sci U S A / Year: 2021 Title: Design of proteasome inhibitors with oral efficacy in vivo against and selectivity over the human proteasome. Authors: Stanley C Xie / Riley D Metcalfe / Hirotake Mizutani / Tanya Puhalovich / Eric Hanssen / Craig J Morton / Yawei Du / Con Dogovski / Shih-Chung Huang / Jeffrey Ciavarri / Paul Hales / Robert ...Authors: Stanley C Xie / Riley D Metcalfe / Hirotake Mizutani / Tanya Puhalovich / Eric Hanssen / Craig J Morton / Yawei Du / Con Dogovski / Shih-Chung Huang / Jeffrey Ciavarri / Paul Hales / Robert J Griffin / Lawrence H Cohen / Bei-Ching Chuang / Sergio Wittlin / Ioanna Deni / Tomas Yeo / Kurt E Ward / Daniel C Barry / Boyin Liu / David L Gillett / Benigno F Crespo-Fernandez / Sabine Ottilie / Nimisha Mittal / Alisje Churchyard / Daniel Ferguson / Anna Caroline C Aguiar / Rafael V C Guido / Jake Baum / Kirsten K Hanson / Elizabeth A Winzeler / Francisco-Javier Gamo / David A Fidock / Delphine Baud / Michael W Parker / Stephen Brand / Lawrence R Dick / Michael D W Griffin / Alexandra E Gould / Leann Tilley / Abstract: The proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the 20S proteasome (20S) β5 active site and ...The proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the 20S proteasome (20S) β5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of compared with a human cell line and exhibit high potency against field isolates of and They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to 20S than to human constitutive 20S (20Sc). Comparison of the cryo-electron microscopy (EM) structures of 20S and 20Sc in complex with MPI-5 and 20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in , underpinning the design of potent and selective antimalarial proteasome inhibitors. | |||||||||
History |
|
-Structure visualization
Movie |
Movie viewer |
---|---|
Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_23574.map.gz | 136.2 MB | EMDB map data format | |
---|---|---|---|---|
Header (meta data) | emd-23574-v30.xml emd-23574.xml | 35.1 KB 35.1 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_23574_fsc.xml | 6.2 KB | Display | FSC data file |
Images | emd_23574.png | 164.1 KB | ||
Others | emd_23574_additional_1.map.gz emd_23574_half_map_1.map.gz emd_23574_half_map_2.map.gz | 78.4 MB 143.9 MB 143.9 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-23574 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-23574 | HTTPS FTP |
-Validation report
Summary document | emd_23574_validation.pdf.gz | 978.2 KB | Display | EMDB validaton report |
---|---|---|---|---|
Full document | emd_23574_full_validation.pdf.gz | 977.8 KB | Display | |
Data in XML | emd_23574_validation.xml.gz | 17.6 KB | Display | |
Data in CIF | emd_23574_validation.cif.gz | 21.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23574 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-23574 | HTTPS FTP |
-Related structure data
Related structure data | 7lxtMC 7lxuC 7lxvC M: atomic model generated by this map C: citing same article (ref.) |
---|---|
Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
---|---|
Related items in Molecule of the Month |
-Map
File | Download / File: emd_23574.map.gz / Format: CCP4 / Size: 155.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Main EM map used for refinement | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.31 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
|
-Supplemental data
-Additional map: Additional map
File | emd_23574_additional_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | Additional map | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: half-volume 1
File | emd_23574_half_map_1.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | half-volume 1 | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Half map: half-volume 2
File | emd_23574_half_map_2.map | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Annotation | half-volume 2 | ||||||||||||
Projections & Slices |
| ||||||||||||
Density Histograms |
-Sample components
+Entire : Plasmodium falciparum 20S proteasome complexed with bortezomib
+Supramolecule #1: Plasmodium falciparum 20S proteasome complexed with bortezomib
+Macromolecule #1: 20S proteasome alpha-1 subunit
+Macromolecule #2: 20S proteasome alpha-2 subunit
+Macromolecule #3: 20S proteasome alpha-3 subunit
+Macromolecule #4: 20S proteasome alpha-4 subunit
+Macromolecule #5: 20S proteasome alpha-5 subunit
+Macromolecule #6: 20S proteasome alpha-6 subunit
+Macromolecule #7: 20S proteasome alpha-7 subunit
+Macromolecule #8: 20S proteasome beta-1 subunit
+Macromolecule #9: 20S proteasome beta-2 subunit
+Macromolecule #10: 20S proteasome beta-3 subunit
+Macromolecule #11: 20S proteasome beta-4 subunit
+Macromolecule #12: 20S proteasome beta-5 subunit
+Macromolecule #13: 20S proteasome beta-6 subunit
+Macromolecule #14: 20S proteasome beta-7 subunit
+Macromolecule #15: N-[(1R)-1-(DIHYDROXYBORYL)-3-METHYLBUTYL]-N-(PYRAZIN-2-YLCARBONYL...
-Experimental details
-Structure determination
Method | cryo EM |
---|---|
Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
---|---|
Grid | Model: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK III |
-Electron microscopy
Microscope | FEI TALOS ARCTICA |
---|---|
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm |
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |