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Yorodumi- PDB-7psa: The acetogenin-bound complex I of Mus musculus resolved to 3.4 an... -
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-Basic information
Entry | Database: PDB / ID: 7psa | |||||||||
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Title | The acetogenin-bound complex I of Mus musculus resolved to 3.4 angstroms | |||||||||
Components |
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Keywords | MEMBRANE PROTEIN / inhibitor-bound / detergent-solubilised / NADH:Ubiquinone oxidoreductase | |||||||||
Function / homology | Function and homology information response to injury involved in regulation of muscle adaptation / Mitochondrial Fatty Acid Beta-Oxidation / Complex I biogenesis / reproductive system development / Mitochondrial protein import / Respiratory electron transport / Glyoxylate metabolism and glycine degradation / RHOG GTPase cycle / respiratory system process / protein insertion into mitochondrial inner membrane ...response to injury involved in regulation of muscle adaptation / Mitochondrial Fatty Acid Beta-Oxidation / Complex I biogenesis / reproductive system development / Mitochondrial protein import / Respiratory electron transport / Glyoxylate metabolism and glycine degradation / RHOG GTPase cycle / respiratory system process / protein insertion into mitochondrial inner membrane / response to light intensity / blastocyst hatching / circulatory system development / ubiquinone-6 biosynthetic process / cellular response to oxygen levels / iron-sulfur cluster assembly complex / psychomotor behavior / mitochondrial large ribosomal subunit binding / gliogenesis / neural precursor cell proliferation / [2Fe-2S] cluster assembly / mitochondrial respirasome / NADH dehydrogenase activity / cardiac muscle tissue development / oxygen sensor activity / respiratory chain complex I / cellular respiration / adult walking behavior / negative regulation of non-canonical NF-kappaB signal transduction / ubiquinone binding / cellular response to glucocorticoid stimulus / positive regulation of mitochondrial membrane potential / acyl binding / response to hydroperoxide / mitochondrial ribosome / electron transport coupled proton transport / iron-sulfur cluster assembly / mitochondrial ATP synthesis coupled electron transport / acyl carrier activity / mitochondrial translation / adult behavior / dopamine metabolic process / NADH:ubiquinone reductase (H+-translocating) / positive regulation of ATP biosynthetic process / proton motive force-driven mitochondrial ATP synthesis / mitochondrial respiratory chain complex I / apoptotic mitochondrial changes / mitochondrial respiratory chain complex I assembly / mitochondrial electron transport, NADH to ubiquinone / electron transport chain / NADH dehydrogenase (ubiquinone) activity / neuron development / quinone binding / ATP synthesis coupled electron transport / cellular response to interferon-beta / negative regulation of intrinsic apoptotic signaling pathway / aerobic respiration / ATP metabolic process / negative regulation of reactive oxygen species biosynthetic process / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / response to cAMP / response to organonitrogen compound / tricarboxylic acid cycle / ionotropic glutamate receptor binding / respiratory electron transport chain / reactive oxygen species metabolic process / visual perception / Neutrophil degranulation / cerebellum development / mitochondrion organization / neurogenesis / response to hormone / response to cocaine / fatty acid metabolic process / regulation of mitochondrial membrane potential / response to nicotine / synaptic membrane / muscle contraction / kidney development / apoptotic signaling pathway / mitochondrial membrane / sensory perception of sound / regulation of protein phosphorylation / brain development / multicellular organism growth / response to hydrogen peroxide / mitochondrial intermembrane space / 2 iron, 2 sulfur cluster binding / negative regulation of cell growth / response to organic cyclic compound / cognition / circadian rhythm / positive regulation of protein catabolic process / NAD binding / positive regulation of fibroblast proliferation / FMN binding / myelin sheath / nervous system development / 4 iron, 4 sulfur cluster binding Similarity search - Function | |||||||||
Biological species | Mus musculus (house mouse) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å | |||||||||
Authors | Grba, D. / Hirst, J. | |||||||||
Funding support | United Kingdom, 2items
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Citation | Journal: J Biol Chem / Year: 2022 Title: Cryo-electron microscopy reveals how acetogenins inhibit mitochondrial respiratory complex I. Authors: Daniel N Grba / James N Blaza / Hannah R Bridges / Ahmed-Noor A Agip / Zhan Yin / Masatoshi Murai / Hideto Miyoshi / Judy Hirst / Abstract: Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a crucial enzyme in energy metabolism, captures the redox potential energy from NADH oxidation/ubiquinone reduction to create the proton ...Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a crucial enzyme in energy metabolism, captures the redox potential energy from NADH oxidation/ubiquinone reduction to create the proton motive force used to drive ATP synthesis in oxidative phosphorylation. High-resolution single-particle electron cryo-EM analyses have provided detailed structural knowledge of the catalytic machinery of complex I, but not of the molecular principles of its energy transduction mechanism. Although ubiquinone is considered to bind in a long channel at the interface of the membrane-embedded and hydrophilic domains, with channel residues likely involved in coupling substrate reduction to proton translocation, no structures with the channel fully occupied have yet been described. Here, we report the structure (determined by cryo-EM) of mouse complex I with a tight-binding natural product acetogenin inhibitor, which resembles the native substrate, bound along the full length of the expected ubiquinone-binding channel. Our structure reveals the mode of acetogenin binding and the molecular basis for structure-activity relationships within the acetogenin family. It also shows that acetogenins are such potent inhibitors because they are highly hydrophobic molecules that contain two specific hydrophilic moieties spaced to lock into two hydrophilic regions of the otherwise hydrophobic channel. The central hydrophilic section of the channel does not favor binding of the isoprenoid chain when the native substrate is fully bound but stabilizes the ubiquinone/ubiquinol headgroup as it transits to/from the active site. Therefore, the amphipathic nature of the channel supports both tight binding of the amphipathic inhibitor and rapid exchange of the ubiquinone/ubiquinol substrate and product. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7psa.cif.gz | 2.7 MB | Display | PDBx/mmCIF format |
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PDB format | pdb7psa.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 7psa.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ps/7psa ftp://data.pdbj.org/pub/pdb/validation_reports/ps/7psa | HTTPS FTP |
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-Related structure data
Related structure data | 13611MC 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 |
EM raw data | EMPIAR-10927 (Title: Single particle cryo-EM dataset of Mus musculus mitochondrial complex I bound with an acetogenin inhibitor Data size: 3.3 TB Data #1: Single-particle cryo-EM dataset of Mus musculus mitochondrial complex I co-purified with the inhibitor acetogenin [micrographs - multiframe]) |
-Links
-Assembly
Deposited unit |
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1 |
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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) Mus musculus (house mouse) 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) Mus musculus (house mouse) 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) Mus musculus (house mouse) 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) Mus musculus (house mouse) 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) Mus musculus (house mouse) 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) Mus musculus (house mouse) 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) Mus musculus (house mouse) 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) Mus musculus (house mouse) 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) Mus musculus (house mouse) 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) Mus musculus (house mouse) 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) Mus musculus (house mouse) 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) Mus musculus (house mouse) / References: UniProt: Q9CXZ1 |
#18: Protein | Mass: 13041.828 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: P52503 |
#30: Protein | Mass: 12675.772 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q99LY9 |
-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) Mus musculus (house mouse) 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) Mus musculus (house mouse) 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) Mus musculus (house mouse) / References: UniProt: Q8BK30 |
-Protein , 2 types, 3 molecules GTU
#7: Protein | Mass: 79866.688 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) 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) Mus musculus (house mouse) / References: UniProt: Q9CR21 |
-NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit ... , 12 types, 12 molecules OPSVWXYZabqr
#15: Protein | Mass: 40657.375 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q99LC3 |
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#16: Protein | Mass: 42588.129 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9DC69 |
#19: Protein | Mass: 10932.675 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9CQ75 |
#21: Protein | Mass: 13380.719 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9CPP6 |
#22: Protein | Mass: 15311.858 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9CQZ5 |
#23: Protein | Mass: 20025.127 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9DCJ5 |
#24: Protein | Mass: 15130.416 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9D8B4 |
#25: Protein | Mass: 16881.588 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9ERS2 |
#26: Protein | Mass: 8149.524 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: O35683 |
#27: Protein | Mass: 9338.867 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9CQ91 |
#42: Protein | Mass: 17154.453 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q7TMF3 |
#43: Protein | Mass: 12637.629 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9Z1P6 |
-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) Mus musculus (house mouse) / References: UniProt: Q9CQY9 |
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#29: Protein | Mass: 14185.692 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9CQ54 |
-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) Mus musculus (house mouse) / References: UniProt: P0DN34 |
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#32: Protein | Mass: 17463.727 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: O09111 |
#33: Protein | Mass: 21742.197 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9CQH3 |
#34: Protein | Mass: 15540.085 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q3UIU2 |
#35: Protein | Mass: 11982.437 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9CPU2 |
#36: Protein | Mass: 11714.240 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9CQZ6 |
#37: Protein | Mass: 21903.828 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9D6J5 |
#38: Protein | Mass: 15105.287 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9CQC7 |
#39: Protein | Mass: 22020.123 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9CQJ8 |
#40: Protein | Mass: 16360.804 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9CR61 |
#41: Protein | Mass: 21054.832 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / References: UniProt: Q9DCS9 |
-Non-polymers , 11 types, 35 molecules
#45: Chemical | ChemComp-SF4 / #46: Chemical | ChemComp-PC1 / #47: Chemical | #48: Chemical | ChemComp-FMN / | #49: Chemical | ChemComp-3PE / #50: Chemical | ChemComp-88I / ( | #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 |
-Sample preparation
Component | Name: Mitochondrial NADH:ubiquinone oxidoreductase from Mus musculus Type: COMPLEX Details: Solubilised in DDM detergent. Native purification via anion exchange, with inhibitor acetogenin added, and size-exclusion chromatography. Entity ID: #1-#44 / Source: NATURAL | ||||||||||||||||
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Molecular weight | Experimental value: NO | ||||||||||||||||
Source (natural) | Organism: Mus musculus (house mouse) | ||||||||||||||||
Buffer solution | pH: 7.55 / Details: pH 7.55 at 25 degrees Celsius | ||||||||||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||
Specimen support | Details: 20 mA glow discharge. Followed by a 2-day PEGylation with a PEG-thiol reagent. Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R0.6/1 | ||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277.15 K |
-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: SPOT SCAN |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 130000 X / Nominal defocus max: 2700 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm |
Specimen holder | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 10 sec. / Electron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1286 |
EM imaging optics | Energyfilter slit width: 20 eV |
Image scans | Movie frames/image: 50 |
-Processing
Software |
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 114209 | ||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 15754 / Details: Generated with a mask in RELION / Num. of class averages: 1 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Space: REAL | ||||||||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 6ZR2 |