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- EMDB-14277: Bovine complex I in the presence of IM1761092, deactive class ii ... -
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Open data
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Basic information
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Title | Bovine complex I in the presence of IM1761092, deactive class ii (Composite map) | |||||||||
![]() | Composite map of 3 focus refinements | |||||||||
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Function / homology | ![]() Complex I biogenesis / Mitochondrial protein import / RHOG GTPase cycle / ubiquinone biosynthetic process / Respiratory electron transport / cellular response to oxygen levels / mitochondrial large ribosomal subunit binding / gliogenesis / neural precursor cell proliferation / [2Fe-2S] cluster assembly ...Complex I biogenesis / Mitochondrial protein import / RHOG GTPase cycle / ubiquinone biosynthetic process / Respiratory electron transport / cellular response to oxygen levels / mitochondrial large ribosomal subunit binding / gliogenesis / neural precursor cell proliferation / [2Fe-2S] cluster assembly / oxygen sensor activity / Neutrophil degranulation / mitochondrial ATP synthesis coupled electron transport / Mitochondrial protein degradation / acyl binding / ubiquinone binding / acyl carrier activity / electron transport coupled proton transport / NADH:ubiquinone reductase (H+-translocating) / NADH dehydrogenase activity / mitochondrial electron transport, NADH to ubiquinone / mitochondrial respiratory chain complex I assembly / respiratory chain complex I / NADH dehydrogenase (ubiquinone) activity / quinone binding / ATP synthesis coupled electron transport / response to cAMP / reactive oxygen species metabolic process / aerobic respiration / fatty acid binding / respiratory electron transport chain / neurogenesis / electron transport chain / mitochondrial membrane / brain development / mitochondrial intermembrane space / 2 iron, 2 sulfur cluster binding / circadian rhythm / NAD binding / fatty acid biosynthetic process / FMN binding / 4 iron, 4 sulfur cluster binding / response to oxidative stress / oxidoreductase activity / mitochondrial inner membrane / mitochondrial matrix / negative regulation of DNA-templated transcription / apoptotic process / protein-containing complex binding / mitochondrion / nucleoplasm / metal ion binding / cytoplasm Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.4 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 | ![]() | 1019.4 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 63.4 KB 63.4 KB | Display Display | ![]() |
Images | ![]() | 102.4 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 592.2 KB | Display | ![]() |
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Full document | ![]() | 591.7 KB | Display | |
Data in XML | ![]() | 9.3 KB | Display | |
Data in CIF | ![]() | 10.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7r46MC ![]() 7qsdC ![]() 7r41C ![]() 7r42C ![]() 7r43C ![]() 7r44C ![]() 7r45C ![]() 7r47C ![]() 7r48C ![]() 7r4cC ![]() 7r4dC ![]() 7r4fC ![]() 7r4gC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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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: 0.731 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)
+Supramolecule #1: NADH Ubiquinone oxidoreductase (Complex I)
+Macromolecule #1: NADH-ubiquinone oxidoreductase chain 3
+Macromolecule #2: NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial
+Macromolecule #3: NADH dehydrogenase [ubiquinone] iron-sulfur protein 3, mitochondrial
+Macromolecule #4: NADH dehydrogenase [ubiquinone] iron-sulfur protein 2, mitochondrial
+Macromolecule #5: NADH dehydrogenase [ubiquinone] flavoprotein 2, mitochondrial
+Macromolecule #6: NADH dehydrogenase [ubiquinone] flavoprotein 1, mitochondrial
+Macromolecule #7: NADH-ubiquinone oxidoreductase 75 kDa subunit, mitochondrial
+Macromolecule #8: NADH-ubiquinone oxidoreductase chain 1
+Macromolecule #9: NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, mitochondrial
+Macromolecule #10: NADH-ubiquinone oxidoreductase chain 6
+Macromolecule #11: NADH-ubiquinone oxidoreductase chain 4L
+Macromolecule #12: NADH-ubiquinone oxidoreductase chain 5
+Macromolecule #13: NADH-ubiquinone oxidoreductase chain 4
+Macromolecule #14: NADH-ubiquinone oxidoreductase chain 2
+Macromolecule #15: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10, mi...
+Macromolecule #16: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 9, mit...
+Macromolecule #17: NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial
+Macromolecule #18: NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial
+Macromolecule #19: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 2
+Macromolecule #20: Acyl carrier protein, mitochondrial
+Macromolecule #21: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 5
+Macromolecule #22: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 6
+Macromolecule #23: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 8
+Macromolecule #24: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11
+Macromolecule #25: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13
+Macromolecule #26: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1
+Macromolecule #27: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3
+Macromolecule #28: NADH dehydrogenase [ubiquinone] 1 subunit C1, mitochondrial
+Macromolecule #29: NADH dehydrogenase [ubiquinone] 1 subunit C2
+Macromolecule #30: NADH dehydrogenase [ubiquinone] iron-sulfur protein 5
+Macromolecule #31: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 1
+Macromolecule #32: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 11, mit...
+Macromolecule #33: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 5, mito...
+Macromolecule #34: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 6
+Macromolecule #35: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 2, mito...
+Macromolecule #36: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 3
+Macromolecule #37: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 8, mito...
+Macromolecule #38: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 4
+Macromolecule #39: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 9
+Macromolecule #40: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 7
+Macromolecule #41: NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10
+Macromolecule #42: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12
+Macromolecule #43: NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 7
+Macromolecule #44: NADH dehydrogenase [ubiquinone] flavoprotein 3, mitochondrial
+Macromolecule #45: DODECYL-BETA-D-MALTOSIDE
+Macromolecule #46: 1,2-Distearoyl-sn-glycerophosphoethanolamine
+Macromolecule #47: IRON/SULFUR CLUSTER
+Macromolecule #48: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
+Macromolecule #49: FE2/S2 (INORGANIC) CLUSTER
+Macromolecule #50: FLAVIN MONONUCLEOTIDE
+Macromolecule #51: POTASSIUM ION
+Macromolecule #52: 1-carbamimidoyl-3-[2-(3-chloranyl-4-iodanyl-phenyl)ethyl]guanidine
+Macromolecule #53: CARDIOLIPIN
+Macromolecule #54: GUANOSINE-5'-TRIPHOSPHATE
+Macromolecule #55: MAGNESIUM ION
+Macromolecule #56: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
+Macromolecule #57: ZINC ION
+Macromolecule #58: ~{S}-[2-[3-[[(2~{R})-3,3-dimethyl-2-oxidanyl-4-phosphonooxy-butan...
+Macromolecule #59: MYRISTIC ACID
+Macromolecule #60: water
-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 K3 BIOQUANTUM (6k x 4k) / Detector mode: COUNTING / Average electron dose: 40.0 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: 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 reconstruction | Resolution.type: BY AUTHOR / Resolution: 2.4 Å / Resolution method: OTHER / Details: D99 measure from PHENIX / Number images used: 35448 |
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Initial angle assignment | Type: PROJECTION MATCHING |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |