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Yorodumi- EMDB-10462: Leishmania tarentolae proteasome 20S subunit complexed with LXE408 -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-10462 | |||||||||
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Title | Leishmania tarentolae proteasome 20S subunit complexed with LXE408 | |||||||||
Map data | ||||||||||
Sample |
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Keywords | Proteasome complex / inhibitor / peptidase / hydrolase | |||||||||
Function / homology | Function and homology information phosphoenolpyruvate carboxykinase activity / proteasome core complex / proteasome endopeptidase 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 / gluconeogenesis / ubiquitin-dependent protein catabolic process ...phosphoenolpyruvate carboxykinase activity / proteasome core complex / proteasome endopeptidase 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 / gluconeogenesis / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / hydrolase activity / protein kinase activity / protein phosphorylation / ATP binding / nucleus / cytoplasm Similarity search - Function | |||||||||
Biological species | Leishmania donovani (eukaryote) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||
Authors | Srinivas H | |||||||||
Citation | Journal: J Med Chem / Year: 2020 Title: Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases. Authors: Advait Nagle / Agnes Biggart / Celine Be / Honnappa Srinivas / Andreas Hein / Diana Caridha / Richard J Sciotti / Brandon Pybus / Mara Kreishman-Deitrick / Badry Bursulaya / Yin H Lai / Mu- ...Authors: Advait Nagle / Agnes Biggart / Celine Be / Honnappa Srinivas / Andreas Hein / Diana Caridha / Richard J Sciotti / Brandon Pybus / Mara Kreishman-Deitrick / Badry Bursulaya / Yin H Lai / Mu-Yun Gao / Fang Liang / Casey J N Mathison / Xiaodong Liu / Vince Yeh / Jeffrey Smith / Isabelle Lerario / Yongping Xie / Donatella Chianelli / Michael Gibney / Ashley Berman / Yen-Liang Chen / Jan Jiricek / Lauren C Davis / Xianzhong Liu / Jaime Ballard / Shilpi Khare / Fabian Kurt Eggimann / Alexandre Luneau / Todd Groessl / Michael Shapiro / Wendy Richmond / Kevin Johnson / Patrick J Rudewicz / Srinivasa P S Rao / Christopher Thompson / Tove Tuntland / Glen Spraggon / Richard J Glynne / Frantisek Supek / Christian Wiesmann / Valentina Molteni / Abstract: Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we ...Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_10462.map.gz | 12.6 MB | EMDB map data format | |
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Header (meta data) | emd-10462-v30.xml emd-10462.xml | 32 KB 32 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_10462_fsc.xml | 10.8 KB | Display | FSC data file |
Images | emd_10462.png | 156.1 KB | ||
Masks | emd_10462_msk_1.map | 103 MB | Mask map | |
Filedesc metadata | emd-10462.cif.gz | 8.7 KB | ||
Others | emd_10462_half_map_1.map.gz emd_10462_half_map_2.map.gz | 79.3 MB 79.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-10462 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-10462 | HTTPS FTP |
-Related structure data
Related structure data | 6tczMC 6td5C M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_10462.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Voxel size | X=Y=Z: 0.852 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_10462_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_10462_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_10462_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
+Entire : Leishmania tarentolae proteasome 20S subunit complex
+Supramolecule #1: Leishmania tarentolae proteasome 20S subunit complex
+Macromolecule #1: Proteasome subunit alpha type
+Macromolecule #2: Proteasome subunit alpha type
+Macromolecule #3: Proteasome subunit alpha type
+Macromolecule #4: Proteasome endopeptidase complex
+Macromolecule #5: Proteasome subunit alpha type
+Macromolecule #6: Proteasome subunit alpha type
+Macromolecule #7: Proteasome endopeptidase complex
+Macromolecule #8: Proteasome subunit beta
+Macromolecule #9: Proteasome subunit beta
+Macromolecule #10: Proteasome subunit beta
+Macromolecule #11: Proteasome subunit family protein
+Macromolecule #12: Proteasome subunit beta
+Macromolecule #13: Proteasome subunit beta
+Macromolecule #14: Proteasome subunit beta
+Macromolecule #15: ~{N}-[4-fluoranyl-3-[6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5...
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 3 mg/mL |
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Buffer | pH: 7.5 |
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 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |