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Yorodumi- EMDB-15025: Leishmania tarentolae proteasome 20S subunit in complex with comp... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-15025 | |||||||||
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Title | Leishmania tarentolae proteasome 20S subunit in complex with compound 2 | |||||||||
Map data | coot contour level | |||||||||
Sample |
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Keywords | proteasome. Cryo-EM / Inhibitor / HYDROLASE | |||||||||
Function / homology | Function and homology information proteasome core complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteasomal protein catabolic process / proteolysis involved in protein catabolic process / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / nucleus ...proteasome core complex / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteasomal protein catabolic process / proteolysis involved in 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 | Leishmania tarentolae (eukaryote) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.7 Å | |||||||||
Authors | Srinivas H | |||||||||
Funding support | 1 items
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Citation | Journal: J Med Chem / Year: 2022 Title: Discovery of Novel Quinoline-Based Proteasome Inhibitors for Human African Trypanosomiasis (HAT). Authors: Dennis C Koester / Vanessa M Marx / Sarah Williams / Jan Jiricek / Maxime Dauphinais / Olivier René / Sarah L Miller / Lei Zhang / Debjani Patra / Yen-Liang Chen / Harry Cheung / Jonathan ...Authors: Dennis C Koester / Vanessa M Marx / Sarah Williams / Jan Jiricek / Maxime Dauphinais / Olivier René / Sarah L Miller / Lei Zhang / Debjani Patra / Yen-Liang Chen / Harry Cheung / Jonathan Gable / Suresh B Lakshminarayana / Colin Osborne / Jean-Rene Galarneau / Upendra Kulkarni / Wendy Richmond / Angela Bretz / Linda Xiao / Frantisek Supek / Christian Wiesmann / Srinivas Honnappa / Celine Be / Pascal Mäser / Marcel Kaiser / Ryan Ritchie / Michael P Barrett / Thierry T Diagana / Christopher Sarko / Srinivasa P S Rao / Abstract: Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo- ...Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an model to predict the brain-to-plasma partition coefficient as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios () to cure a CNS disease such as HAT. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_15025.map.gz | 95.5 MB | EMDB map data format | |
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Header (meta data) | emd-15025-v30.xml emd-15025.xml | 31.8 KB 31.8 KB | Display Display | EMDB header |
Images | emd_15025.png | 51.4 KB | ||
Filedesc metadata | emd-15025.cif.gz | 8.2 KB | ||
Others | emd_15025_additional_1.map.gz emd_15025_half_map_1.map.gz emd_15025_half_map_2.map.gz | 95.8 MB 46.1 MB 46.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-15025 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-15025 | HTTPS FTP |
-Validation report
Summary document | emd_15025_validation.pdf.gz | 1015 KB | Display | EMDB validaton report |
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Full document | emd_15025_full_validation.pdf.gz | 1014.6 KB | Display | |
Data in XML | emd_15025_validation.xml.gz | 13.7 KB | Display | |
Data in CIF | emd_15025_validation.cif.gz | 16.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-15025 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-15025 | HTTPS FTP |
-Related structure data
Related structure data | 7zyjMC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_15025.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | coot contour level | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.86 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: coot contour level
File | emd_15025_additional_1.map | ||||||||||||
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Annotation | coot contour level | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: coot contour level
File | emd_15025_half_map_1.map | ||||||||||||
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Annotation | coot contour level | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: coot contour level
File | emd_15025_half_map_2.map | ||||||||||||
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Annotation | coot contour level | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
+Entire : Proteasome
+Supramolecule #1: Proteasome
+Macromolecule #1: Proteasome subunit alpha type
+Macromolecule #2: Proteasome subunit alpha type
+Macromolecule #3: Proteasome subunit alpha type
+Macromolecule #4: Proteasome subunit alpha type
+Macromolecule #5: Proteasome alpha 5 subunit, putative
+Macromolecule #6: Proteasome alpha 1 subunit, putative
+Macromolecule #7: Proteasome alpha 7 subunit, putative
+Macromolecule #8: Proteasome subunit beta
+Macromolecule #9: Proteasome subunit beta
+Macromolecule #10: Proteasome subunit beta
+Macromolecule #11: Proteasome subunit beta
+Macromolecule #12: Proteasome subunit beta
+Macromolecule #13: Proteasome beta 6 subunit, putative
+Macromolecule #14: Proteasome subunit beta
+Macromolecule #15: ~{N}-cyclopentyl-6-methyl-4-phenylazanyl-quinoline-2-carboxamide
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 2 mg/mL |
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Buffer | pH: 7 |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 1.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 20.0 µm / Nominal defocus min: 1.0 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 260000 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: cisTEM (ver. 1.0) |