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- PDB-6ztq: Cryo-EM structure of respiratory complex I from Mus musculus inhi... -
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Basic information
Entry | Database: PDB / ID: 6ztq | ||||||||||||
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Title | Cryo-EM structure of respiratory complex I from Mus musculus inhibited by piericidin A at 3.0 A | ||||||||||||
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![]() | OXIDOREDUCTASE / NADH / ubiquinone / complex I | ||||||||||||
Function / homology | ![]() response to injury involved in regulation of muscle adaptation / Protein lipoylation / Mitochondrial Fatty Acid Beta-Oxidation / Complex I biogenesis / reproductive system development / Mitochondrial protein import / Respiratory electron transport / RHOG GTPase cycle / protein insertion into mitochondrial inner membrane / circulatory system development ...response to injury involved in regulation of muscle adaptation / Protein lipoylation / Mitochondrial Fatty Acid Beta-Oxidation / Complex I biogenesis / reproductive system development / Mitochondrial protein import / Respiratory electron transport / RHOG GTPase cycle / protein insertion into mitochondrial inner membrane / circulatory system development / blastocyst hatching / respiratory system process / psychomotor behavior / Mitochondrial protein degradation / cellular response to oxygen levels / iron-sulfur cluster assembly complex / response to light intensity / mitochondrial large ribosomal subunit binding / gliogenesis / neural precursor cell proliferation / cardiac muscle tissue development / negative regulation of non-canonical NF-kappaB signal transduction / : / [2Fe-2S] cluster assembly / oxygen sensor activity / adult walking behavior / cellular response to glucocorticoid stimulus / ubiquinone-6 biosynthetic process / positive regulation of mitochondrial membrane potential / respiratory chain complex I / response to hydroperoxide / cellular respiration / iron-sulfur cluster assembly / NADH dehydrogenase activity / mitochondrial ribosome / adult behavior / dopamine metabolic process / positive regulation of ATP biosynthetic process / mitochondrial translation / NADH:ubiquinone reductase (H+-translocating) / positive regulation of execution phase of apoptosis / apoptotic mitochondrial changes / mitochondrial ATP synthesis coupled electron transport / : / mitochondrial electron transport, NADH to ubiquinone / mitochondrial respiratory chain complex I assembly / proton motive force-driven mitochondrial ATP synthesis / acyl binding / ubiquinone binding / NADH dehydrogenase (ubiquinone) activity / acyl carrier activity / cellular response to interferon-beta / neuron development / quinone binding / electron transport coupled proton transport / ATP synthesis coupled electron transport / negative regulation of intrinsic apoptotic signaling pathway / muscle contraction / negative regulation of reactive oxygen species biosynthetic process / ATP metabolic process / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / tricarboxylic acid cycle / : / visual perception / ionotropic glutamate receptor binding / aerobic respiration / Neutrophil degranulation / respiratory electron transport chain / reactive oxygen species metabolic process / neurogenesis / cerebellum development / response to hormone / regulation of mitochondrial membrane potential / mitochondrion organization / fatty acid metabolic process / response to cocaine / kidney development / synaptic membrane / mitochondrial membrane / apoptotic signaling pathway / electron transport chain / sensory perception of sound / regulation of protein phosphorylation / response to nicotine / brain development / response to hydrogen peroxide / multicellular organism growth / response to organic cyclic compound / mitochondrial intermembrane space / negative regulation of cell growth / cognition / 2 iron, 2 sulfur cluster binding / circadian rhythm / positive regulation of protein catabolic process / NAD binding / FMN binding / myelin sheath / nervous system development / 4 iron, 4 sulfur cluster binding Similarity search - Function | ||||||||||||
Biological species | ![]() ![]() | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å | ||||||||||||
![]() | Bridges, H.R. / Blaza, J.N. / Agip, A.N.A. / Hirst, J. | ||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Structure of inhibitor-bound mammalian complex I. Authors: Hannah R Bridges / Justin G Fedor / James N Blaza / Andrea Di Luca / Alexander Jussupow / Owen D Jarman / John J Wright / Ahmed-Noor A Agip / Ana P Gamiz-Hernandez / Maxie M Roessler / Ville ...Authors: Hannah R Bridges / Justin G Fedor / James N Blaza / Andrea Di Luca / Alexander Jussupow / Owen D Jarman / John J Wright / Ahmed-Noor A Agip / Ana P Gamiz-Hernandez / Maxie M Roessler / Ville R I Kaila / Judy Hirst / ![]() ![]() ![]() Abstract: Respiratory complex I (NADH:ubiquinone oxidoreductase) captures the free energy from oxidising NADH and reducing ubiquinone to drive protons across the mitochondrial inner membrane and power ...Respiratory complex I (NADH:ubiquinone oxidoreductase) captures the free energy from oxidising NADH and reducing ubiquinone to drive protons across the mitochondrial inner membrane and power oxidative phosphorylation. Recent cryo-EM analyses have produced near-complete models of the mammalian complex, but leave the molecular principles of its long-range energy coupling mechanism open to debate. Here, we describe the 3.0-Å resolution cryo-EM structure of complex I from mouse heart mitochondria with a substrate-like inhibitor, piericidin A, bound in the ubiquinone-binding active site. We combine our structural analyses with both functional and computational studies to demonstrate competitive inhibitor binding poses and provide evidence that two inhibitor molecules bind end-to-end in the long substrate binding channel. Our findings reveal information about the mechanisms of inhibition and substrate reduction that are central for understanding the principles of energy transduction in mammalian complex I. | ||||||||||||
History |
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Structure visualization
Movie |
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Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 1.5 MB | Display | ![]() |
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PDB format | ![]() | 1.2 MB | Display | ![]() |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
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Links
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Assembly
Deposited unit | ![]()
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Components
-NADH-ubiquinone oxidoreductase chain ... , 7 types, 7 molecules AHJKLMN
#1: Protein | Mass: 13251.785 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: P03899, NADH:ubiquinone reductase (H+-translocating) |
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#8: Protein | Mass: 36105.027 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: P03888, NADH:ubiquinone reductase (H+-translocating) |
#10: Protein | Mass: 18656.100 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: P03925, NADH:ubiquinone reductase (H+-translocating) |
#11: Protein | Mass: 10637.629 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: P03903, NADH:ubiquinone reductase (H+-translocating) |
#12: Protein | Mass: 68547.297 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: P03921, NADH:ubiquinone reductase (H+-translocating) |
#13: Protein | Mass: 51943.547 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: P03911, NADH:ubiquinone reductase (H+-translocating) |
#14: Protein | Mass: 38800.230 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: P03893, NADH:ubiquinone reductase (H+-translocating) |
-NADH dehydrogenase [ubiquinone] iron-sulfur protein ... , 7 types, 7 molecules BCDIQRe
#2: Protein | Mass: 24715.912 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: Q9DC70, NADH:ubiquinone reductase (H+-translocating) |
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#3: Protein | Mass: 30191.307 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: Q9DCT2, NADH:ubiquinone reductase (H+-translocating) |
#4: Protein | Mass: 52720.602 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: Q91WD5, NADH:ubiquinone reductase (H+-translocating) |
#9: Protein | Mass: 24068.355 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: Q8K3J1, NADH:ubiquinone reductase (H+-translocating) |
#17: Protein | Mass: 19814.725 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#18: Protein | Mass: 13041.828 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#30: Protein | Mass: 12675.772 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-NADH dehydrogenase [ubiquinone] flavoprotein ... , 3 types, 3 molecules EFs
#5: Protein | Mass: 27318.336 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: Q9D6J6, NADH:ubiquinone reductase (H+-translocating) |
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#6: Protein | Mass: 50904.152 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: Q91YT0, NADH:ubiquinone reductase (H+-translocating) |
#44: Protein | Mass: 11833.504 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-Protein , 3 types, 4 molecules GTUY
#7: Protein | Mass: 79866.688 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() References: UniProt: Q91VD9, NADH:ubiquinone reductase (H+-translocating) | ||
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#20: Protein | Mass: 17390.289 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() #24: Protein | | Mass: 15130.416 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit ... , 11 types, 11 molecules OPSVWXZabqr
#15: Protein | Mass: 40657.375 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#16: Protein | Mass: 42588.129 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#19: Protein | Mass: 10932.675 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#21: Protein | Mass: 13380.719 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#22: Protein | Mass: 15311.858 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#23: Protein | Mass: 20025.127 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#25: Protein | Mass: 16881.588 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#26: Protein | Mass: 8149.524 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#27: Protein | Mass: 9338.867 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#42: Protein | Mass: 17154.453 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#43: Protein | Mass: 12637.629 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-NADH dehydrogenase [ubiquinone] 1 subunit ... , 2 types, 2 molecules cd
#28: Protein | Mass: 8636.023 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#29: Protein | Mass: 14185.692 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit ... , 11 types, 11 molecules fghijklmnop
#31: Protein | Mass: 6965.109 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#32: Protein | Mass: 17463.727 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#33: Protein | Mass: 21742.197 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#34: Protein | Mass: 15582.122 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#35: Protein | Mass: 11982.437 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#36: Protein | Mass: 11714.240 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#37: Protein | Mass: 21903.828 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#38: Protein | Mass: 15105.287 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#39: Protein | Mass: 22020.123 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#40: Protein | Mass: 16360.804 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#41: Protein | Mass: 21054.832 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-Non-polymers , 11 types, 35 molecules ![](data/chem/img/SF4.gif)
![](data/chem/img/PC1.gif)
![](data/chem/img/HQH.gif)
![](data/chem/img/3PE.gif)
![](data/chem/img/FES.gif)
![](data/chem/img/FMN.gif)
![](data/chem/img/CDL.gif)
![](data/chem/img/ATP.gif)
![](data/chem/img/NDP.gif)
![](data/chem/img/ZN.gif)
![](data/chem/img/EHZ.gif)
![](data/chem/img/PC1.gif)
![](data/chem/img/HQH.gif)
![](data/chem/img/3PE.gif)
![](data/chem/img/FES.gif)
![](data/chem/img/FMN.gif)
![](data/chem/img/CDL.gif)
![](data/chem/img/ATP.gif)
![](data/chem/img/NDP.gif)
![](data/chem/img/ZN.gif)
![](data/chem/img/EHZ.gif)
#45: Chemical | ChemComp-SF4 / #46: Chemical | ChemComp-PC1 / #47: Chemical | ChemComp-HQH / | #48: Chemical | ChemComp-3PE / #49: Chemical | #50: Chemical | ChemComp-FMN / | #51: Chemical | ChemComp-CDL / #52: Chemical | ChemComp-ATP / | #53: Chemical | ChemComp-NDP / | #54: Chemical | ChemComp-ZN / | #55: Chemical | |
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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 |
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Sample preparation
Component | Name: Respiratory complex I / Type: COMPLEX / Entity ID: #1-#44 / Source: NATURAL | ||||||||||||||||||||
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Molecular weight | Value: 0.98 MDa / Experimental value: NO | ||||||||||||||||||||
Source (natural) | Organism: ![]() ![]() | ||||||||||||||||||||
Buffer solution | pH: 7.14 / Details: pH corrected at room temperature | ||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 4.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||
Specimen support | Details: The grid was treated for 48 hours in an anaerobic glovebox in ethanol containing 5mM 11-mercaptoundecylhexaethyleneglycol, washed three times in ethanol and air dried prior to use. Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R0.6/1 | ||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Details: blot for 10 seconds before plunging |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal magnification: 47600 X / Nominal defocus max: 3400 nm / Nominal defocus min: 2200 nm / Cs: 2.7 mm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 |
EM imaging optics | Energyfilter slit width: 20 eV |
Image scans | Width: 3838 / Height: 3710 / Movie frames/image: 24 / Used frames/image: 1-12 |
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Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||
3D reconstruction | Resolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 27193 / Algorithm: FOURIER SPACE / Symmetry type: POINT | ||||||||||||||||||||
Atomic model building | Protocol: OTHER / Space: REAL | ||||||||||||||||||||
Refinement | Highest resolution: 3 Å |