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Open data
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Basic information
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Title | Bovine complex I in the active state at 3.1 A (Composite map) | |||||||||
![]() | Composite map of 3 focus refinements | |||||||||
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Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.8 Å | |||||||||
![]() | Bridges HR / Blaza JN / Yin Z / Chung I / Hirst J | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 325.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 17.5 KB 17.5 KB | Display Display | ![]() |
Images | ![]() | 88.2 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 641.8 KB | Display | ![]() |
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Full document | ![]() | 641.3 KB | Display | |
Data in XML | ![]() | 7.7 KB | Display | |
Data in CIF | ![]() | 8.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7qsdC ![]() 7r41C ![]() 7r42C ![]() 7r43C ![]() 7r44C ![]() 7r45C ![]() 7r46C ![]() 7r47C ![]() 7r48C ![]() 7r4cC ![]() 7r4dC ![]() 7r4fC ![]() 7r4gC C: citing same article ( |
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Links
EMDB pages | ![]() ![]() |
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Map
File | ![]() | ||||||||||||||||||||||||||||||||||||
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Annotation | Composite map of 3 focus refinements | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.056 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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Sample components
-Entire : NADH Ubiquinone oxidoreductase (Complex I)
Entire | Name: NADH Ubiquinone oxidoreductase (Complex I) |
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Components |
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-Supramolecule #1: NADH Ubiquinone oxidoreductase (Complex I)
Supramolecule | Name: NADH Ubiquinone oxidoreductase (Complex I) / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#45 |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 1 MDa |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 3 mg/mL | ||||||||||||
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Buffer | pH: 7.14 Component:
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Grid | Model: 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. | ||||||||||||
Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.5 µm / Nominal defocus min: 1.5 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: OTHER / Details: D99 measure from Phenix / Number images used: 18231 |
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Initial angle assignment | Type: PROJECTION MATCHING |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |