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- EMDB-11002: CryoEM structure of bovine cytochrome bc1 in complex with a tetra... -

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Basic information

Entry
Database: EMDB / ID: EMD-11002
TitleCryoEM structure of bovine cytochrome bc1 in complex with a tetrahydroquinolone inhibitor
Map dataCytochrome bc1 map with bound JAG inhibitor
Sample
  • Complex: Cytochrome bc1Coenzyme Q – cytochrome c reductase
Biological speciesBos taurus (cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsMuench SP / Johnson R / Amporndanai K / Atonyuk S
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Wellcome Trust109158/B/15/Z United Kingdom
CitationJournal: 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
DepositionMay 5, 2020-
Header (metadata) releaseJul 22, 2020-
Map releaseJul 22, 2020-
UpdateMay 26, 2021-
Current statusMay 26, 2021Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.9
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.9
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_11002.png

Downloads & links

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Map

FileDownload / File: emd_11002.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCytochrome bc1 map with bound JAG inhibitor
Voxel sizeX=Y=Z: 1.065 Å
Density
Contour LevelBy AUTHOR: 0.9 / Movie #1: 0.9
Minimum - Maximum-1.2754788 - 3.682574
Average (Standard dev.)0.04360874 (±0.20853026)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 213.00002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0651.0651.065
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z213.000213.000213.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-1.2753.6830.044

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Supplemental data

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Sample components

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Entire : Cytochrome bc1

EntireName: Cytochrome bc1Coenzyme Q – cytochrome c reductase
Components
  • Complex: Cytochrome bc1Coenzyme Q – cytochrome c reductase

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Supramolecule #1: Cytochrome bc1

SupramoleculeName: Cytochrome bc1 / type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Bos taurus (cattle) / Tissue: Heart / Organelle: mitochondria
Molecular weightExperimental: 480 KDa

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration5 mg/mL
BufferpH: 7.5
GridModel: C-flat-1.2/1.3 4C / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV / Details: 6 second blot, blot force 6.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm 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
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 430009
CTF correctionSoftware - Name: MotionCorr2
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 211916

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT

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