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Yorodumi- PDB-7r4d: Bovine complex I in the presence of IM1761092, deactive class vi ... -
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-Basic information
Entry | Database: PDB / ID: 7r4d | |||||||||
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Title | Bovine complex I in the presence of IM1761092, deactive class vi (Composite map) | |||||||||
Components |
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Keywords | OXIDOREDUCTASE / Complex I | |||||||||
Function / homology | Function and homology information Complex I biogenesis / Mitochondrial protein import / RHOG GTPase cycle / cellular response to oxygen levels / mitochondrial large ribosomal subunit binding / Respiratory electron transport / gliogenesis / neural precursor cell proliferation / : / [2Fe-2S] cluster assembly ...Complex I biogenesis / Mitochondrial protein import / RHOG GTPase cycle / cellular response to oxygen levels / mitochondrial large ribosomal subunit binding / Respiratory electron transport / gliogenesis / neural precursor cell proliferation / : / [2Fe-2S] cluster assembly / oxygen sensor activity / ubiquinone-6 biosynthetic process / cellular respiration / Neutrophil degranulation / NADH dehydrogenase activity / mitochondrial ribosome / mitochondrial translation / Mitochondrial protein degradation / NADH:ubiquinone reductase (H+-translocating) / apoptotic mitochondrial changes / acyl binding / ubiquinone binding / acyl carrier activity / quinone binding / electron transport coupled proton transport / neurogenesis / ATP synthesis coupled electron transport / negative regulation of intrinsic apoptotic signaling pathway / ATP metabolic process / mitochondrial ATP synthesis coupled electron transport / mitochondrial respiratory chain complex I assembly / response to cAMP / respiratory electron transport chain / reactive oxygen species metabolic process / regulation of mitochondrial membrane potential / : / mitochondrial electron transport, NADH to ubiquinone / fatty acid binding / NADH dehydrogenase (ubiquinone) activity / apoptotic signaling pathway / electron transport chain / regulation of protein phosphorylation / brain development / mitochondrial membrane / aerobic respiration / mitochondrial intermembrane space / negative regulation of cell growth / 2 iron, 2 sulfur cluster binding / fatty acid biosynthetic process / positive regulation of fibroblast proliferation / NAD binding / FMN binding / 4 iron, 4 sulfur cluster binding / response to oxidative stress / oxidoreductase activity / mitochondrial inner membrane / structural constituent of ribosome / mitochondrial matrix / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / protein-containing complex binding / mitochondrion / nucleoplasm / metal ion binding / cytoplasm Similarity search - Function | |||||||||
Biological species | Bos taurus (cattle) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.3 Å | |||||||||
Authors | Bridges, H.R. / Blaza, J.N. / Yin, Z. / Chung, I. / Hirst, J. | |||||||||
Funding support | United Kingdom, 2items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7r4d.cif.gz | 1.5 MB | Display | PDBx/mmCIF format |
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PDB format | pdb7r4d.ent.gz | 1.2 MB | Display | PDB format |
PDBx/mmJSON format | 7r4d.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7r4d_validation.pdf.gz | 2.7 MB | Display | wwPDB validaton report |
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Full document | 7r4d_full_validation.pdf.gz | 2.8 MB | Display | |
Data in XML | 7r4d_validation.xml.gz | 205.4 KB | Display | |
Data in CIF | 7r4d_validation.cif.gz | 316 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/r4/7r4d ftp://data.pdbj.org/pub/pdb/validation_reports/r4/7r4d | HTTPS FTP |
-Related structure data
Related structure data | 14297MC 7qsdC 7r41C 7r42C 7r43C 7r44C 7r45C 7r46C 7r47C 7r48C 7r4cC 7r4fC 7r4gC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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-Components
-NADH-ubiquinone oxidoreductase chain ... , 7 types, 7 molecules AHJKLMN
#1: Protein | Mass: 13086.531 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: Q7JAS9, NADH:ubiquinone reductase (H+-translocating) |
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#8: Protein | Mass: 35716.785 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: P03887 |
#10: Protein | Mass: 19110.488 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: P03924, NADH:ubiquinone reductase (H+-translocating) |
#11: Protein | Mass: 10828.195 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: P03902, NADH:ubiquinone reductase (H+-translocating) |
#12: Protein | Mass: 68355.930 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: P03920, NADH:ubiquinone reductase (H+-translocating) |
#13: Protein | Mass: 52158.758 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: P03910, NADH:ubiquinone reductase (H+-translocating) |
#14: Protein | Mass: 39302.941 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: P03892, NADH:ubiquinone reductase (H+-translocating) |
-NADH dehydrogenase [ubiquinone] iron-sulfur protein ... , 7 types, 7 molecules BCDIQRe
#2: Protein | Mass: 23802.926 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: P42026, NADH:ubiquinone reductase (H+-translocating) |
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#3: Protein | Mass: 30323.445 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: P23709, NADH:ubiquinone reductase (H+-translocating) |
#4: Protein | Mass: 52678.547 Da / Num. of mol.: 1 / Mutation: Q166R / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: P17694, NADH:ubiquinone reductase (H+-translocating) |
#9: Protein | Mass: 23926.400 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) References: UniProt: P42028, NADH:ubiquinone reductase (H+-translocating) |
#17: Protein | Mass: 19841.555 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02375 |
#18: Protein | Mass: 13433.194 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: P23934 |
#30: Protein | Mass: 12694.671 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02379 |
-NADH dehydrogenase [ubiquinone] flavoprotein ... , 3 types, 3 molecules EFs
#5: Protein | Mass: 27341.496 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: P04394, NADH:ubiquinone reductase (H+-translocating), NADH dehydrogenase |
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#6: Protein | Mass: 50718.777 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: P25708, NADH:ubiquinone reductase (H+-translocating), NADH dehydrogenase |
#44: Protein | Mass: 11874.492 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: P25712 |
-Protein , 2 types, 3 molecules GTU
#7: Protein | Mass: 79532.219 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart References: UniProt: P15690, NADH:ubiquinone reductase (H+-translocating) |
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#20: Protein | Mass: 17421.340 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: P52505 |
-NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit ... , 12 types, 12 molecules OPSVWXYZabqr
#15: Protein | Mass: 39330.984 Da / Num. of mol.: 1 / Mutation: N278K / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: P34942 |
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#16: Protein | Mass: 42913.430 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: P34943 |
#19: Protein | Mass: 11097.824 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02370 |
#21: Protein | Mass: 13334.608 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: P23935 |
#22: Protein | Mass: 15083.544 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02366 |
#23: Protein | Mass: 20124.133 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: P42029 |
#24: Protein | Mass: 14814.058 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q8HXG6 |
#25: Protein | Mass: 16694.395 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q95KV7 |
#26: Protein | Mass: 8117.445 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02377 |
#27: Protein | Mass: 9357.850 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02371 |
#42: Protein | Mass: 17115.508 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: O97725 |
#43: Protein | Mass: 12737.620 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q05752 |
-NADH dehydrogenase [ubiquinone] 1 subunit ... , 2 types, 2 molecules cd
#28: Protein | Mass: 8796.211 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02376 |
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#29: Protein | Mass: 14159.332 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02827 |
-NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit ... , 11 types, 11 molecules fghijklmnop
#31: Protein | Mass: 6978.148 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02378 |
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#32: Protein | Mass: 17594.945 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q8HXG5 |
#33: Protein | Mass: 21624.135 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02380 |
#34: Protein | Mass: 15460.927 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02367 |
#35: Protein | Mass: 12298.858 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02374 |
#36: Protein | Mass: 11160.705 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02365 |
#37: Protein | Mass: 21678.459 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02372 |
#38: Protein | Mass: 15206.260 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: P48305 |
#39: Protein | Mass: 21827.889 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02369 |
#40: Protein | Mass: 16428.846 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02368 |
#41: Protein | Mass: 21000.900 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / Organ: Heart / References: UniProt: Q02373 |
-Sugars , 1 types, 13 molecules
#45: Sugar | ChemComp-LMT / |
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-Non-polymers , 15 types, 1643 molecules
#46: Chemical | ChemComp-3PE / #47: Chemical | ChemComp-SF4 / #48: Chemical | #49: Chemical | #50: Chemical | ChemComp-FMN / | #51: Chemical | ChemComp-K / | #52: Chemical | ChemComp-CDL / #53: Chemical | ChemComp-I49 / | #54: Chemical | ChemComp-GTP / | #55: Chemical | ChemComp-MG / | #56: Chemical | ChemComp-NDP / | #57: Chemical | ChemComp-ZN / | #58: Chemical | #59: Chemical | ChemComp-MYR / | #60: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: NADH Ubiquinone oxidoreductase (Complex I) / Type: COMPLEX / Entity ID: #1-#44 / Source: NATURAL | ||||||||||||||||||||
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Molecular weight | Value: 1 MDa / Experimental value: YES | ||||||||||||||||||||
Source (natural) | Organism: Bos taurus (cattle) / Organ: Heart | ||||||||||||||||||||
Buffer solution | pH: 7.14 | ||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||
Specimen support | Details: Grid also covalently modified by peg-thiol for 48 hours in a nitrogen atmosphere. Grid type: UltrAuFoil R0.6/1 | ||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm |
Image recording | Electron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) |
-Processing
EM software | Name: RELION / Version: 3.1 / Category: particle selection |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
3D reconstruction | Resolution: 2.3 Å / Resolution method: OTHER / Num. of particles: 122019 / Details: D99 measure from phenix / Symmetry type: POINT |