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- EMDB-14128: Bovine complex I in the active state at 3.1 A (Composite map) -

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Basic information

Entry
Database: EMDB / ID: EMD-14128
TitleBovine complex I in the active state at 3.1 A (Composite map)
Map dataComposite map of 3 focus refinements
Sample
  • Complex: NADH Ubiquinone oxidoreductase (Complex I)
Biological speciesBos taurus (cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 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
DepositionJan 13, 2022-
Header (metadata) releaseFeb 8, 2023-
Map releaseFeb 8, 2023-
UpdateFeb 15, 2023-
Current statusFeb 15, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14128.png

Downloads & links

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Map

FileDownload / File: emd_14128.map.gz / Format: CCP4 / Size: 347.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite map of 3 focus refinements
Voxel sizeX=Y=Z: 1.056 Å
Density
Contour LevelBy AUTHOR: 4.38
Minimum - Maximum-11.44264 - 21.84333
Average (Standard dev.)0.002739492 (±1.0149832)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions450450450
Spacing450450450
CellA=B=C: 475.2 Å
α=β=γ: 90.0 °

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Supplemental data

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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 (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 mMC4H12ClNO3Tris-HClTris
150.0 mMNaClSodium chlorideSodium Chloride
0.05 %C24H46O11dodecylmaltoside
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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 3.5 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: OTHER / Details: D99 measure from Phenix / Number images used: 18231

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