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- EMDB-16963: Leishmania tarentolae proteasome 20S subunit in complex with 1-Be... -
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Open data
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Basic information
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Title | Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide | |||||||||
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![]() | Proteasome 20S subunit / UNKNOWN FUNCTION | |||||||||
Function / homology | ![]() proteasome core complex / proteasome core complex, beta-subunit complex / proteasomal protein catabolic process / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / 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 / proteasomal protein catabolic process / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteolysis involved in protein catabolic process / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / endopeptidase activity / nucleus / cytoplasm / cytosol Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.59 Å | |||||||||
![]() | Rowland P | |||||||||
Funding support | 1 items
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![]() | ![]() Title: Structure-Guided Design and Synthesis of a Pyridazinone Series of Proteasome Inhibitors. Authors: Michael G Thomas / Kate McGonagle / Paul Rowland / David A Robinson / Peter G Dodd / Isabel Camino-Díaz / Lorna Campbell / Juan Cantizani / Pablo Castañeda / Daniel Conn / Peter D Craggs / ...Authors: Michael G Thomas / Kate McGonagle / Paul Rowland / David A Robinson / Peter G Dodd / Isabel Camino-Díaz / Lorna Campbell / Juan Cantizani / Pablo Castañeda / Daniel Conn / Peter D Craggs / Darren Edwards / Liam Ferguson / Andrew Fosberry / Laura Frame / Panchali Goswami / Xiao Hu / Justyna Korczynska / Lorna MacLean / Julio Martin / Nicole Mutter / Maria Osuna-Cabello / Christy Paterson / Imanol Peña / Erika G Pinto / Caterina Pont / Jennifer Riley / Yoko Shishikura / Frederick R C Simeons / Laste Stojanovski / John Thomas / Karolina Wrobel / Robert J Young / Filip Zmuda / Fabio Zuccotto / Kevin D Read / Ian H Gilbert / Maria Marco / Timothy J Miles / Pilar Manzano / Manu De Rycker / ![]() Abstract: There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, ...There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the proteasome. A related analogue, active against , showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 11.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 31 KB 31 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 10.6 KB | Display | ![]() |
Images | ![]() | 156.8 KB | ||
Others | ![]() ![]() | 79.4 MB 79.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 811 KB | Display | ![]() |
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Full document | ![]() | 810.6 KB | Display | |
Data in XML | ![]() | 18.1 KB | Display | |
Data in CIF | ![]() | 23.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8oluMC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.07 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Flipped half map to correspond with the final map
File | emd_16963_half_map_1.map | ||||||||||||
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Annotation | Flipped half map to correspond with the final map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Flipped half map to correspond with the final map
File | emd_16963_half_map_2.map | ||||||||||||
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Annotation | Flipped half map to correspond with the final map | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
+Entire : Leishmania tarentolae proteasome 20S subunit in complex with 1-Be...
+Supramolecule #1: Leishmania tarentolae proteasome 20S subunit in complex with 1-Be...
+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}-[3-(cyclopropylcarbamoyl)phenyl]-6-oxidanylidene-1-(phenylme...
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Average electron dose: 30.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.4 µm / Nominal defocus min: 1.8 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Initial model | Chain - Source name: Other / Chain - Initial model type: experimental model / Details: Unpublished model |
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Refinement | Protocol: FLEXIBLE FIT |
Output model | ![]() PDB-8olu: |