[English] 日本語
Yorodumi- PDB-7b93: Cryo-EM structure of mitochondrial complex I from Mus musculus in... -
+Open data
-Basic information
Entry | Database: PDB / ID: 7b93 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Cryo-EM structure of mitochondrial complex I from Mus musculus inhibited by IACS-2858 at 3.0 A | |||||||||
Components |
| |||||||||
Keywords | OXIDOREDUCTASE / Inhibitor / Ubiquinone / Complex I | |||||||||
Function / homology | Function and homology information response to injury involved in regulation of muscle adaptation / reproductive system development / Protein lipoylation / Mitochondrial Fatty Acid Beta-Oxidation / Complex I biogenesis / Mitochondrial protein import / RHOG GTPase cycle / Respiratory electron transport / protein insertion into mitochondrial inner membrane / blastocyst hatching ...response to injury involved in regulation of muscle adaptation / reproductive system development / Protein lipoylation / Mitochondrial Fatty Acid Beta-Oxidation / Complex I biogenesis / Mitochondrial protein import / RHOG GTPase cycle / Respiratory electron transport / protein insertion into mitochondrial inner membrane / blastocyst hatching / circulatory system development / respiratory system process / psychomotor behavior / Mitochondrial protein degradation / response to light intensity / cellular response to oxygen levels / iron-sulfur cluster assembly complex / ubiquinone-6 biosynthetic process / mitochondrial large ribosomal subunit binding / gliogenesis / cellular response to glucocorticoid stimulus / neural precursor cell proliferation / cardiac muscle tissue development / : / negative regulation of non-canonical NF-kappaB signal transduction / [2Fe-2S] cluster assembly / adult walking behavior / oxygen sensor activity / positive regulation of mitochondrial membrane potential / response to hydroperoxide / cellular respiration / : / respiratory chain complex I / mitochondrial ribosome / iron-sulfur cluster assembly / adult behavior / mitochondrial translation / ubiquinone binding / positive regulation of ATP biosynthetic process / dopamine metabolic process / positive regulation of execution phase of apoptosis / NADH:ubiquinone reductase (H+-translocating) / proton motive force-driven mitochondrial ATP synthesis / NADH dehydrogenase activity / apoptotic mitochondrial changes / : / mitochondrial ATP synthesis coupled electron transport / mitochondrial electron transport, NADH to ubiquinone / mitochondrial respiratory chain complex I assembly / neuron development / electron transport coupled proton transport / acyl binding / cellular response to interferon-beta / acyl carrier activity / NADH dehydrogenase (ubiquinone) activity / quinone binding / cellular response to retinoic acid / ATP synthesis coupled electron transport / negative regulation of intrinsic apoptotic signaling pathway / negative regulation of reactive oxygen species biosynthetic process / muscle contraction / ATP metabolic process / extrinsic apoptotic signaling pathway / tricarboxylic acid cycle / ionotropic glutamate receptor binding / visual perception / aerobic respiration / response to hormone / Neutrophil degranulation / neurogenesis / respiratory electron transport chain / reactive oxygen species metabolic process / cerebellum development / kidney development / regulation of mitochondrial membrane potential / response to cocaine / mitochondrion organization / cognition / synaptic membrane / fatty acid metabolic process / response to nicotine / apoptotic signaling pathway / mitochondrial membrane / sensory perception of sound / electron transport chain / brain development / regulation of protein phosphorylation / response to hydrogen peroxide / multicellular organism growth / response to organic cyclic compound / negative regulation of cell growth / mitochondrial intermembrane space / 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 | Mus musculus (house mouse) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.04 Å | |||||||||
Authors | Chung, I. / Hirst, J. | |||||||||
Funding support | United Kingdom, 2items
| |||||||||
Citation | Journal: Sci Adv / Year: 2021 Title: Cork-in-bottle mechanism of inhibitor binding to mammalian complex I. Authors: Injae Chung / Riccardo Serreli / Jason B Cross / M Emilia Di Francesco / Joseph R Marszalek / Judy Hirst / Abstract: Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia- ...Mitochondrial complex I (NADH:ubiquinone oxidoreductase), a major contributor of free energy for oxidative phosphorylation, is increasingly recognized as a promising drug target for ischemia-reperfusion injury, metabolic disorders, and various cancers. Several pharmacologically relevant but structurally unrelated small molecules have been identified as specific complex I inhibitors, but their modes of action remain unclear. Here, we present a 3.0-Å resolution cryo-electron microscopy structure of mammalian complex I inhibited by a derivative of IACS-010759, which is currently in clinical development against cancers reliant on oxidative phosphorylation, revealing its unique cork-in-bottle mechanism of inhibition. We combine structural and kinetic analyses to deconvolute cross-species differences in inhibition and identify the structural motif of a "chain" of aromatic rings as a characteristic that promotes inhibition. Our findings provide insights into the importance of π-stacking residues for inhibitor binding in the long substrate-binding channel in complex I and a guide for future biorational drug design. | |||||||||
History |
|
-Structure visualization
Movie |
Movie viewer |
---|---|
Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7b93.cif.gz | 1.5 MB | Display | PDBx/mmCIF format |
---|---|---|---|---|
PDB format | pdb7b93.ent.gz | 1.2 MB | Display | PDB format |
PDBx/mmJSON format | 7b93.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7b93_validation.pdf.gz | 2.6 MB | Display | wwPDB validaton report |
---|---|---|---|---|
Full document | 7b93_full_validation.pdf.gz | 2.6 MB | Display | |
Data in XML | 7b93_validation.xml.gz | 222.5 KB | Display | |
Data in CIF | 7b93_validation.cif.gz | 328.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/b9/7b93 ftp://data.pdbj.org/pub/pdb/validation_reports/b9/7b93 | HTTPS FTP |
-Related structure data
Related structure data | 12095MC M: map data used to model this data C: citing same article (ref.) |
---|---|
Similar structure data |
-Links
-Assembly
Deposited unit |
|
---|---|
1 |
|
-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) / Tissue: heart References: UniProt: P03899, NADH:ubiquinone reductase (H+-translocating) |
---|---|
#8: Protein | Mass: 36105.027 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Tissue: heart 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) / Tissue: heart 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) / Tissue: heart 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) / Tissue: heart 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) / Tissue: heart 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) / Tissue: heart 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) / Tissue: heart References: UniProt: Q9DC70, NADH:ubiquinone reductase (H+-translocating) |
---|---|
#3: Protein | Mass: 30191.307 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Tissue: heart 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) / Tissue: heart 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) / Tissue: heart 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart References: UniProt: Q9D6J6, NADH:ubiquinone reductase (H+-translocating) |
---|---|
#6: Protein | Mass: 50904.152 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Tissue: heart 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) / Tissue: heart / References: UniProt: Q8BK30 |
-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) Mus musculus (house mouse) / Tissue: heart References: UniProt: Q91VD9, NADH:ubiquinone reductase (H+-translocating) | ||
---|---|---|---|
#20: Protein | Mass: 17390.289 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Tissue: heart / References: UniProt: Q9CR21 #24: Protein | | Mass: 15130.416 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Tissue: heart / References: UniProt: G5E814 |
-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) Mus musculus (house mouse) / Tissue: heart / References: UniProt: Q99LC3 |
---|---|
#16: Protein | Mass: 42588.129 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / References: UniProt: Q9DCJ5 |
#25: Protein | Mass: 16881.588 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / References: UniProt: Q9CQY9 |
---|---|
#29: Protein | Mass: 14185.692 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Tissue: heart / 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) / Tissue: heart / References: UniProt: P0DN34 |
---|---|
#32: Protein | Mass: 17463.727 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Mus musculus (house mouse) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / 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) / Tissue: heart / References: UniProt: Q9DCS9 |
-Non-polymers , 11 types, 35 molecules
#45: Chemical | ChemComp-SF4 / #46: Chemical | ChemComp-PC1 / #47: Chemical | ChemComp-3PE / #48: Chemical | #49: Chemical | ChemComp-FMN / | #50: Chemical | ChemComp-T2Q / | #51: Chemical | ChemComp-CDL / #52: Chemical | ChemComp-ATP / | #53: Chemical | ChemComp-NDP / | #54: Chemical | ChemComp-ZN / | #55: Chemical | |
---|
-Details
Has ligand of interest | Y |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Respiratory complex I / Type: COMPLEX Details: Native purification of mitochondrial complex I inhibited by IACS-2858. Entity ID: #1-#44 / Source: NATURAL | ||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Source (natural) | Organism: Mus musculus (house mouse) / Strain: C57BL/6 / Organelle: mitochondria / Tissue: heart | ||||||||||||||||||||
Buffer solution | pH: 7.14 | ||||||||||||||||||||
Buffer component |
| ||||||||||||||||||||
Specimen | 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 DRIED PRIOR TO USE. Grid material: GOLD | ||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K / Details: blot for 10 seconds before plunging |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
---|---|
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 magnification: 130000 X / Nominal defocus max: 2700 nm / Nominal defocus min: 1500 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Electron dose: 52 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 2 |
-Processing
Software | Name: PHENIX / Version: 1.16_3549: / Classification: refinement | ||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
EM software |
| ||||||||||||||||||||||||||||||||||||||||||||
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C1 (asymmetric) | ||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.04 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 44000 / Symmetry type: POINT | ||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Space: REAL | ||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | PDB-ID: 6ZR2 | ||||||||||||||||||||||||||||||||||||||||||||
Refine LS restraints |
|