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- EMDB-14268: Bovine complex I in the presence of IM1761092, active class iv (H... -

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Basic information

Entry
Database: EMDB / ID: EMD-14268
TitleBovine complex I in the presence of IM1761092, active class iv (Hydrophilic domain)
Map dataHydrophilic domain globally sharpened
Sample
  • Complex: NADH Ubiquinone oxidoreductase (Complex I)
Biological speciesBos taurus (domestic cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.41 Å
AuthorsBridges HR / Blaza JN / Yin Z / Chung I / Hirst J
Funding support United Kingdom, 2 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_U105663141 United Kingdom
Medical Research Council (MRC, United Kingdom)MC_UU_00015/2 United Kingdom
CitationJournal: Science / Year: 2023
Title: Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides.
Authors: Hannah R Bridges / James N Blaza / Zhan Yin / Injae Chung / Michael N Pollak / Judy Hirst /
Abstract: The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target ...The molecular mode of action of biguanides, including the drug metformin, which is widely used in the treatment of diabetes, is incompletely characterized. Here, we define the inhibitory drug-target interaction(s) of a model biguanide with mammalian respiratory complex I by combining cryo-electron microscopy and enzyme kinetics. We interpret these data to explain the selectivity of biguanide binding to different enzyme states. The primary inhibitory site is in an amphipathic region of the quinone-binding channel, and an additional binding site is in a pocket on the intermembrane-space side of the enzyme. An independent local chaotropic interaction, not previously described for any drug, displaces a portion of a key helix in the membrane domain. Our data provide a structural basis for biguanide action and enable the rational design of medicinal biguanides.
History
DepositionFeb 8, 2022-
Header (metadata) releaseFeb 8, 2023-
Map releaseFeb 8, 2023-
UpdateFeb 8, 2023-
Current statusFeb 8, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14268.png

Downloads & links

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Map

FileDownload / File: emd_14268.map.gz / Format: CCP4 / Size: 1.1 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHydrophilic domain globally sharpened
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 660 pix.
= 482.46 Å		0.73 Å/pix.
x 660 pix.
= 482.46 Å		0.73 Å/pix.
x 660 pix.
= 482.46 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.731 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.018
Minimum - Maximum-0.042042837 - 0.11611702
Average (Standard dev.)-0.00020549024 (±0.0032982149)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions660660660
Spacing660660660
CellA=B=C: 482.46 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_14268_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Hydrophilic domain halfmap1

Fileemd_14268_half_map_1.map
AnnotationHydrophilic domain halfmap1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Hydrophilic domain halfmap2

Fileemd_14268_half_map_2.map
AnnotationHydrophilic domain halfmap2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : NADH Ubiquinone oxidoreductase (Complex I)

EntireName: NADH Ubiquinone oxidoreductase (Complex I)
Components
  • Complex: NADH Ubiquinone oxidoreductase (Complex I)

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Supramolecule #1: NADH Ubiquinone oxidoreductase (Complex I)

SupramoleculeName: NADH Ubiquinone oxidoreductase (Complex I) / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#45
Source (natural)Organism: Bos taurus (domestic cattle) / Organ: Heart
Molecular weightTheoretical: 1 MDa

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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

Concentration3 mg/mL
BufferpH: 7.14
Component:
ConcentrationFormulaName
20.0 mMC4H11NO3Tris
150.0 mMNaClSodium Chloride
0.05 %C24H46O11n-Dodecyl-B-D-Maltoside
GridModel: UltrAuFoil R0.6/1 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 90 sec. / Pretreatment - Atmosphere: AIR
Details: Grid also covalently modified by peg-thiol for 48 hours in a nitrogen atmosphere.
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Detector mode: COUNTING / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.41 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 31957
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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