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Yorodumi- EMDB-11002: CryoEM structure of bovine cytochrome bc1 in complex with a tetra... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-11002 | |||||||||
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Title | CryoEM structure of bovine cytochrome bc1 in complex with a tetrahydroquinolone inhibitor | |||||||||
Map data | Cytochrome bc1 map with bound JAG inhibitor | |||||||||
Sample |
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Biological species | Bos taurus (cattle) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.8 Å | |||||||||
Authors | Muench SP / Johnson R / Amporndanai K / Atonyuk S | |||||||||
Funding support | United Kingdom, 1 items
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Citation | Journal: Front Cell Infect Microbiol / Year: 2020 Title: Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites. Authors: Martin J McPhillie / Ying Zhou / Mark R Hickman / James A Gordon / Christopher R Weber / Qigui Li / Patty J Lee / Kangsa Amporndanai / Rachel M Johnson / Heather Darby / Stuart Woods / Zhu- ...Authors: Martin J McPhillie / Ying Zhou / Mark R Hickman / James A Gordon / Christopher R Weber / Qigui Li / Patty J Lee / Kangsa Amporndanai / Rachel M Johnson / Heather Darby / Stuart Woods / Zhu-Hong Li / Richard S Priestley / Kurt D Ristroph / Scott B Biering / Kamal El Bissati / Seungmin Hwang / Farida Esaa Hakim / Sarah M Dovgin / Joseph D Lykins / Lucy Roberts / Kerrie Hargrave / Hua Cong / Anthony P Sinai / Stephen P Muench / Jitender P Dubey / Robert K Prud'homme / Hernan A Lorenzi / Giancarlo A Biagini / Silvia N Moreno / Craig W Roberts / Svetlana V Antonyuk / Colin W G Fishwick / Rima McLeod / Abstract: Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a ...Apicomplexan infections cause substantial morbidity and mortality, worldwide. New, improved therapies are needed. Herein, we create a next generation anti-apicomplexan lead compound, JAG21, a tetrahydroquinolone, with increased sp3-character to improve parasite selectivity. Relative to other cytochrome inhibitors, JAG21 has improved solubility and ADMET properties, without need for pro-drug. JAG21 significantly reduces tachyzoites and encysted bradyzoites , and in primary and established chronic murine infections. Moreover, JAG21 treatment leads to 100% survival. Further, JAG21 is efficacious against drug-resistant . Causal prophylaxis and radical cure are achieved after sporozoite infection with oral administration of a single dose (2.5 mg/kg) or 3 days treatment at reduced dose (0.625 mg/kg/day), eliminating parasitemia, and leading to 100% survival. Enzymatic, binding, and co-crystallography/pharmacophore studies demonstrate selectivity for apicomplexan relative to mammalian enzymes. JAG21 has significant promise as a pre-clinical candidate for prevention, treatment, and cure of toxoplasmosis and malaria. | |||||||||
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_11002.map.gz | 28.7 MB | EMDB map data format | |
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Header (meta data) | emd-11002-v30.xml emd-11002.xml | 11.2 KB 11.2 KB | Display Display | EMDB header |
Images | emd_11002.png | 72.3 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-11002 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-11002 | HTTPS FTP |
-Validation report
Summary document | emd_11002_validation.pdf.gz | 274.1 KB | Display | EMDB validaton report |
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Full document | emd_11002_full_validation.pdf.gz | 273.2 KB | Display | |
Data in XML | emd_11002_validation.xml.gz | 5.8 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-11002 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-11002 | HTTPS FTP |
-Related 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_11002.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Cytochrome bc1 map with bound JAG inhibitor | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.065 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : Cytochrome bc1
Entire | Name: Cytochrome bc1 |
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Components |
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-Supramolecule #1: Cytochrome bc1
Supramolecule | Name: Cytochrome bc1 / type: complex / ID: 1 / Parent: 0 |
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Source (natural) | Organism: Bos taurus (cattle) / Tissue: Heart / Organelle: mitochondria |
Molecular weight | Experimental: 480 KDa |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 5 mg/mL |
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Buffer | pH: 7.5 |
Grid | Model: C-flat-1.2/1.3 4C / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV / Details: 6 second blot, blot force 6. |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON III (4k x 4k) / Detector mode: INTEGRATING / Number grids imaged: 1 / Number real images: 5356 / Average electron dose: 66.4 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 |
+Image processing
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: FLEXIBLE FIT |
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