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Yorodumi- EMDB-12095: Cryo-EM structure of mitochondrial complex I from Mus musculus in... -
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-Basic information
Entry | Database: EMDB / ID: EMD-12095 | |||||||||
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Title | Cryo-EM structure of mitochondrial complex I from Mus musculus inhibited by IACS-2858 at 3.0 A | |||||||||
Map data | Globally sharpened and filtered map from RELION's PostProcess tool | |||||||||
Sample |
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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 / psychomotor behavior / mitochondrial large ribosomal subunit binding / iron-sulfur cluster assembly complex / gliogenesis / neural precursor cell proliferation / mitochondrial respirasome / NADH dehydrogenase activity / cardiac muscle tissue development / [2Fe-2S] cluster assembly / oxygen sensor activity / respiratory chain complex I / cellular respiration / negative regulation of non-canonical NF-kappaB signal transduction / adult walking behavior / 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 / mitochondrial ATP synthesis coupled electron transport / iron-sulfur cluster assembly / acyl carrier activity / mitochondrial translation / adult behavior / dopamine metabolic process / NADH:ubiquinone reductase (H+-translocating) / positive regulation of ATP biosynthetic process / mitochondrial respiratory chain complex I / proton motive force-driven mitochondrial ATP synthesis / apoptotic mitochondrial changes / mitochondrial electron transport, NADH to ubiquinone / mitochondrial respiratory chain complex I assembly / electron transport chain / NADH dehydrogenase (ubiquinone) activity / quinone binding / neuron development / ATP synthesis coupled electron transport / cellular response to interferon-beta / negative regulation of intrinsic apoptotic signaling pathway / aerobic respiration / ATP metabolic process / cellular response to retinoic acid / extrinsic apoptotic signaling pathway / negative regulation of reactive oxygen species biosynthetic process / response to cAMP / tricarboxylic acid cycle / response to organonitrogen compound / respiratory electron transport chain / ionotropic glutamate receptor binding / reactive oxygen species metabolic process / visual perception / Neutrophil degranulation / neurogenesis / cerebellum development / mitochondrion organization / response to hormone / fatty acid metabolic process / response to cocaine / regulation of mitochondrial membrane potential / response to nicotine / muscle contraction / synaptic membrane / 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) / Mouse (mice) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.04 Å | |||||||||
Authors | Chung I / Hirst J | |||||||||
Funding support | United Kingdom, 2 items
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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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_12095.map.gz | 324.9 MB | EMDB map data format | |
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Header (meta data) | emd-12095-v30.xml emd-12095.xml | 68.1 KB 68.1 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_12095_fsc.xml | 15.9 KB | Display | FSC data file |
Images | emd_12095.png | 167.2 KB | ||
Masks | emd_12095_msk_1.map | 347.6 MB | Mask map | |
Others | emd_12095_additional_1.map.gz emd_12095_half_map_1.map.gz emd_12095_half_map_2.map.gz | 277.8 MB 278 MB 277.5 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-12095 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-12095 | HTTPS FTP |
-Related structure data
Related structure data | 7b93MC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_12095.map.gz / Format: CCP4 / Size: 347.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Globally sharpened and filtered map from RELION's PostProcess tool | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.055 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
File | emd_12095_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Additional map: Full map from RELION's 3D Refinement tool (unsharpened...
File | emd_12095_additional_1.map | ||||||||||||
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Annotation | Full map from RELION's 3D Refinement tool (unsharpened and unfiltered) | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map 1 from RELION's 3D Refinement tool...
File | emd_12095_half_map_1.map | ||||||||||||
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Annotation | Half map 1 from RELION's 3D Refinement tool (unsharpened and unfiltered) | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map 2 from RELION's 3D Refinement tool...
File | emd_12095_half_map_2.map | ||||||||||||
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Annotation | Half map 2 from RELION's 3D Refinement tool (unsharpened and unfiltered) | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
+Entire : Respiratory complex I
+Supramolecule #1: Respiratory 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: MCG5603
+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: IRON/SULFUR CLUSTER
+Macromolecule #46: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
+Macromolecule #47: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE
+Macromolecule #48: FE2/S2 (INORGANIC) CLUSTER
+Macromolecule #49: FLAVIN MONONUCLEOTIDE
+Macromolecule #50: 1-[[3-(4-methylsulfonylpiperidin-1-yl)phenyl]methyl]-5-[3-[4-(tri...
+Macromolecule #51: CARDIOLIPIN
+Macromolecule #52: ADENOSINE-5'-TRIPHOSPHATE
+Macromolecule #53: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
+Macromolecule #54: ZINC ION
+Macromolecule #55: ~{S}-[2-[3-[[(2~{R})-3,3-dimethyl-2-oxidanyl-4-phosphonooxy-butan...
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.14 Component:
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Grid | Material: GOLD 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. | ||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: blot for 10 seconds before plunging. |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.7 µm / Nominal defocus min: 1.5 µm / Nominal magnification: 130000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 2 / Average electron dose: 52.0 e/Å2 |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |