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- EMDB-21963: CryoEM structure of mouse DUOX1-DUOXA1 complex in the dimer-of-di... -

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Basic information

Entry
Database: EMDB / ID: EMD-21963
TitleCryoEM structure of mouse DUOX1-DUOXA1 complex in the dimer-of-dimer state
Map datacryoEM structure of the mouse DUOX1-DUOXA1 complex in the dimer-of-dimer state
Sample
  • Complex: mouse DUOX1-DUOXA1 complex
    • Protein or peptide: Dual oxidase 1
    • Protein or peptide: Dual oxidase maturation factor 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: HEME C
  • Ligand: 1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE
  • Ligand: DIUNDECYL PHOSPHATIDYL CHOLINE
Function / homology
Function and homology information


regulation of thyroid hormone generation / Thyroxine biosynthesis / NAD(P)H oxidase (H2O2-forming) / cuticle development / positive regulation of hydrogen peroxide biosynthetic process / superoxide-generating NAD(P)H oxidase activity / hormone biosynthetic process / NAD(P)H oxidase H2O2-forming activity / NADPH oxidase complex / thyroid hormone generation ...regulation of thyroid hormone generation / Thyroxine biosynthesis / NAD(P)H oxidase (H2O2-forming) / cuticle development / positive regulation of hydrogen peroxide biosynthetic process / superoxide-generating NAD(P)H oxidase activity / hormone biosynthetic process / NAD(P)H oxidase H2O2-forming activity / NADPH oxidase complex / thyroid hormone generation / superoxide anion generation / hydrogen peroxide biosynthetic process / positive regulation of cell motility / hydrogen peroxide metabolic process / positive regulation of wound healing / cell leading edge / response to cAMP / reactive oxygen species metabolic process / positive regulation of neuron differentiation / hydrogen peroxide catabolic process / peroxidase activity / defense response / protein localization / cytokine-mediated signaling pathway / positive regulation of reactive oxygen species metabolic process / protein transport / regulation of inflammatory response / response to oxidative stress / apical plasma membrane / calcium ion binding / heme binding / endoplasmic reticulum membrane / enzyme binding / cell surface / endoplasmic reticulum / membrane / plasma membrane
Similarity search - Function
Dual oxidase maturation factor / Dual oxidase, peroxidase domain / Dual oxidase maturation factor / Ferric reductase, NAD binding domain / Ferric reductase NAD binding domain / FAD-binding 8 / FAD-binding domain / Ferric reductase transmembrane component-like domain / Ferric reductase like transmembrane component / Haem peroxidase, animal-type ...Dual oxidase maturation factor / Dual oxidase, peroxidase domain / Dual oxidase maturation factor / Ferric reductase, NAD binding domain / Ferric reductase NAD binding domain / FAD-binding 8 / FAD-binding domain / Ferric reductase transmembrane component-like domain / Ferric reductase like transmembrane component / Haem peroxidase, animal-type / Haem peroxidase domain superfamily, animal type / Animal haem peroxidase / Animal heme peroxidase superfamily profile. / EF hand / Haem peroxidase superfamily / FAD-binding domain, ferredoxin reductase-type / Ferredoxin-NADP reductase (FNR), nucleotide-binding domain / Ferredoxin reductase-type FAD binding domain profile. / Riboflavin synthase-like beta-barrel / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair
Similarity search - Domain/homology
NAD(P)H oxidase (H2O2-forming) / Dual oxidase maturation factor 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsSun J
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL143037 United States
CitationJournal: Nat Struct Mol Biol / Year: 2020
Title: Structures of mouse DUOX1-DUOXA1 provide mechanistic insights into enzyme activation and regulation.
Authors: Ji Sun /
Abstract: DUOX1, an NADPH oxidase family member, catalyzes the production of hydrogen peroxide. DUOX1 is expressed in various tissues, including the thyroid and respiratory tract, and plays a crucial role in ...DUOX1, an NADPH oxidase family member, catalyzes the production of hydrogen peroxide. DUOX1 is expressed in various tissues, including the thyroid and respiratory tract, and plays a crucial role in processes such as thyroid hormone biosynthesis and innate host defense. DUOX1 co-assembles with its maturation factor DUOXA1 to form an active enzyme complex. However, the molecular mechanisms for activation and regulation of DUOX1 remain mostly unclear. Here, I present cryo-EM structures of the mammalian DUOX1-DUOXA1 complex, in the absence and presence of substrate NADPH, as well as DUOX1-DUOXA1 in an unexpected dimer-of-dimers configuration. These structures reveal atomic details of the DUOX1-DUOXA1 interaction, a lipid-mediated NADPH-binding pocket and the electron transfer path. Furthermore, biochemical and structural analyses indicate that the dimer-of-dimers configuration represents an inactive state of DUOX1-DUOXA1, suggesting an oligomerization-dependent regulatory mechanism. Together, my work provides structural bases for DUOX1-DUOXA1 activation and regulation.
History
DepositionMay 12, 2020-
Header (metadata) releaseSep 2, 2020-
Map releaseSep 2, 2020-
UpdateMar 17, 2021-
Current statusMar 17, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6wxu
  • Surface level: 0.5
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21963.png

Downloads & links

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Map

FileDownload / File: emd_21963.map.gz / Format: CCP4 / Size: 46.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationcryoEM structure of the mouse DUOX1-DUOXA1 complex in the dimer-of-dimer state
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.5 / Movie #1: 0.5
Minimum - Maximum-2.0208445 - 3.3028708
Average (Standard dev.)0.026868446 (±0.12628445)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions230230230
Spacing230230230
CellA=B=C: 248.40001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.081.081.08
M x/y/z230230230
origin x/y/z0.0000.0000.000
length x/y/z248.400248.400248.400
α/β/γ90.00090.00090.000
start NX/NY/NZ13112264
NX/NY/NZ123151209
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS230230230
D min/max/mean-2.0213.3030.027

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Supplemental data

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Sample components

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Entire : mouse DUOX1-DUOXA1 complex

EntireName: mouse DUOX1-DUOXA1 complex
Components
  • Complex: mouse DUOX1-DUOXA1 complex
    • Protein or peptide: Dual oxidase 1
    • Protein or peptide: Dual oxidase maturation factor 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: HEME C
  • Ligand: 1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE
  • Ligand: DIUNDECYL PHOSPHATIDYL CHOLINE

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Supramolecule #1: mouse DUOX1-DUOXA1 complex

SupramoleculeName: mouse DUOX1-DUOXA1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Homo sapiens (human)
Molecular weightTheoretical: 220 KDa

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Macromolecule #1: Dual oxidase 1

MacromoleculeName: Dual oxidase 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 175.739812 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPSRGAQNSI SWEVQRFDGW YNNLMEHRWG SKGSRLQRLV PASYADGVYQ PLKEPYLPNP RHLSNRVMRG SAGQPSLRNR TVLGVFFGY HVLSDLVSVE TPGCPAEFLN IYIPHGDPVF DPDKRGNVVL PFQRSRWDRN TGQSPSNPRD QSNQVTGWLD G SAIYGSSH ...String:
GPSRGAQNSI SWEVQRFDGW YNNLMEHRWG SKGSRLQRLV PASYADGVYQ PLKEPYLPNP RHLSNRVMRG SAGQPSLRNR TVLGVFFGY HVLSDLVSVE TPGCPAEFLN IYIPHGDPVF DPDKRGNVVL PFQRSRWDRN TGQSPSNPRD QSNQVTGWLD G SAIYGSSH SWSDTLRSFS GGQLASGPDP AFPSDSQSSL LMWMAPDPST GQGGPRGVYA FGAQRGNREP FLQALGLLWF RY HNLCARK LAQEHPHWGD EELFQHARKR VIATYQNIAM YEWLPSFLKQ TPPEYPGYRP FLDPSISPEF VVASEQFLST MVP SGVYMR NASCHFQGIP SHNSSVSGAL RVCNSYWSRE HPKLQRAEDV DALLLGMASQ IAEREDHVVV EDMQDFWPGP LKFS RTDYL ASCLQRGRDL GLPSYTKARE ALGLSPISHW QDINPALSRS NGTVLEATAA LYNQDLSRLE LLPGGLLESH GDPGP LFST IVLDQFVRLR DGDRYWFENT RNGLFSKEEI AEIRNTSLRD ILVAVTNVDP SALQPNVFFW LAGDPCPQPS QLSAKG LPA CAPLFIRDYF EGSGFGFGLT IGTLCCFPLV SLLSAWIVAR LRKRNFKRLQ RQDRQSIMSE KLVGGVEALE WQGRNEP CR PVLVHLQPGQ IRVVDGRLTV LRTIQLRPPQ QVNLILSSNR GRRTLLLKIP KEYDLVLLFN MEEERQALVE NVRGALKE N GLSFQEWELR EQELMRAAVT RQQRGHLLET FFRHLFSQVL DINQADAGTL PLDSSTKVRE ALTCELSRAE FADSLGLKP QDMFVESMFS LADKDGNGYL SFREFLDILV VFMKGSPEEK SRLMFRMYDF DGNGLISKDE FIRMLRSFIE ISNNCLSKAQ LAEVVESMF RESGFQDKEE LTWEDFHFML RDHDSDLRFT QLCVKGVEVP EVIKNLCRRA SYISQEKICP SPRMSAHCAR N NMKTASSP QRLQCPMDTD PPQEIRRRFG KKVTSFQPLL FTEAHREKFQ RSRRHQTVQQ FKRFIENYRR HIGCVAVFYT IT GALFLER AYYYAFAAHH SGITDTTRVG IILSRGTAAS ISFMFSYILL TMCRNLITFL RETFLNRYIP FDAAVDFHRL IAS TAIILT VLHSAGHVVN VYLFSISPLS VLSCLFPGLF HDDGSEFPQK YYWWFFQTVP GLTGVLLLLA LAIMYVFASH HFRR RSFRG FWLTHHLYIF LYILLIIHGS FALIQMPRFH IFFLVPAIIY VGDKLVSLSR KKVEISVVKA ELLPSGVTHL RFQRP QGFE YKSGQWVRIA CLALGTTEYH PFTLTSAPHE DTLSLHIRAA GPWTTRLREI YSPPTGDTCA RYPKLYLDGP FGEGHQ EWH KFEVSVLVGG GIGVTPFASI LKDLVFKSSV SCQVFCKKIY FIWVTRTQRQ FEWLADIIRE VEENDRQDLV SVHIYIT QL AEKFDLRTTM LYICERHFQK VLNRSLFTGL RSITHFGRPP FEPFFNSLQE VHPQVRKIGV FSCGPPGMTK NVEKACQL I NRQDRTHFSH HYENF

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Macromolecule #2: Dual oxidase maturation factor 1

MacromoleculeName: Dual oxidase maturation factor 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 37.619738 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAALGHTLPF YTGTKPTFPM DTTLAVIITI FLTALVTFII ILPGIRGKTR LFWLLRVVTS LFIGAVILAV NFSSEWSVGH VNANTTYKA FSPKWVSVDV GLQIGLGGVN ITLTGTPVQQ LNETINYNEA FAWRLGRSYA EEYAKALEKG LPDPVLYLAE K FTPRSPCG ...String:
MAALGHTLPF YTGTKPTFPM DTTLAVIITI FLTALVTFII ILPGIRGKTR LFWLLRVVTS LFIGAVILAV NFSSEWSVGH VNANTTYKA FSPKWVSVDV GLQIGLGGVN ITLTGTPVQQ LNETINYNEA FAWRLGRSYA EEYAKALEKG LPDPVLYLAE K FTPRSPCG LYNQYRLAGH YASAMLWVAF LCWLLANVML SMPVLVYGGH MLLATGLFQL LALFFFSMTT SLISPCPLRL GT AVLHTHH GPAFWITLAT GLLCILLGLV MAVAHRMQPH RLKAFFNQSS EDPVLEWGSE EGGLLSPHYR SIAESPETQD IPM SVASSE TCFKEEHPKE SDCSL

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 10 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #5: HEME C

MacromoleculeName: HEME C / type: ligand / ID: 5 / Number of copies: 4 / Formula: HEC
Molecular weightTheoretical: 618.503 Da
Chemical component information

ChemComp-HEC:
HEME C / Heme C

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Macromolecule #6: 1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE

MacromoleculeName: 1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE / type: ligand / ID: 6 / Number of copies: 2 / Formula: PX2
Molecular weightTheoretical: 535.671 Da
Chemical component information

ChemComp-PX2:
1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE

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Macromolecule #7: DIUNDECYL PHOSPHATIDYL CHOLINE

MacromoleculeName: DIUNDECYL PHOSPHATIDYL CHOLINE / type: ligand / ID: 7 / Number of copies: 2 / Formula: PLC
Molecular weightTheoretical: 622.834 Da
Chemical component information

ChemComp-PLC:
DIUNDECYL PHOSPHATIDYL CHOLINE / phospholipid*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 65.4 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.13) / Number images used: 302097

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-6wxu:
CryoEM structure of mouse DUOX1-DUOXA1 complex in the dimer-of-dimer state

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