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- EMDB-42013: Structural Basis of Human NOX5 Activation -

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Basic information

Entry
Database: EMDB / ID: EMD-42013
TitleStructural Basis of Human NOX5 Activation
Map data
Sample
  • Complex: NADPH oxidase 5
    • Protein or peptide: NADPH oxidase 5
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
  • Ligand: DODECANE
  • Ligand: DECANE
  • Ligand: NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
  • Ligand: HEME B/C
  • Ligand: ZINC ION
Keywordsenzyme / oxidase / activation mechanism / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of fusion of sperm to egg plasma membrane / superoxide-generating NADPH oxidase activity / Oxidoreductases; Acting on NADH or NADPH; With oxygen as acceptor / superoxide-generating NAD(P)H oxidase activity / cytoskeleton-dependent cytokinesis / NADPH oxidase complex / endothelial cell proliferation / proton channel activity / superoxide anion generation / Detoxification of Reactive Oxygen Species ...regulation of fusion of sperm to egg plasma membrane / superoxide-generating NADPH oxidase activity / Oxidoreductases; Acting on NADH or NADPH; With oxygen as acceptor / superoxide-generating NAD(P)H oxidase activity / cytoskeleton-dependent cytokinesis / NADPH oxidase complex / endothelial cell proliferation / proton channel activity / superoxide anion generation / Detoxification of Reactive Oxygen Species / proton transmembrane transport / positive regulation of cytokine production / defense response / positive regulation of reactive oxygen species metabolic process / NADP binding / flavin adenine dinucleotide binding / angiogenesis / apoptotic process / heme binding / calcium ion binding / endoplasmic reticulum membrane / endoplasmic reticulum / plasma membrane
Similarity search - Function
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 / EF-hand domain / EF hand / FAD-binding domain, ferredoxin reductase-type ...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 / EF-hand domain / EF hand / 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, 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
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.06 Å
AuthorsCui C / Jiang M / Sun J
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM141357 United States
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis of human NOX5 activation.
Authors: Chenxi Cui / Meiqin Jiang / Nikhil Jain / Sourav Das / Yu-Hua Lo / Ali A Kermani / Tanadet Pipatpolkai / Ji Sun /
Abstract: NADPH oxidase 5 (NOX5) catalyzes the production of superoxide free radicals and regulates physiological processes from sperm motility to cardiac rhythm. Overexpression of NOX5 leads to cancers, ...NADPH oxidase 5 (NOX5) catalyzes the production of superoxide free radicals and regulates physiological processes from sperm motility to cardiac rhythm. Overexpression of NOX5 leads to cancers, diabetes, and cardiovascular diseases. NOX5 is activated by intracellular calcium signaling, but the underlying molecular mechanism of which - in particular, how calcium triggers electron transfer from NADPH to FAD - is still unclear. Here we capture motions of full-length human NOX5 upon calcium binding using single-particle cryogenic electron microscopy (cryo-EM). By combining biochemistry, mutagenesis analyses, and molecular dynamics (MD) simulations, we decode the molecular basis of NOX5 activation and electron transfer. We find that calcium binding to the EF-hand domain increases NADPH dynamics, permitting electron transfer between NADPH and FAD and superoxide production. Our structural findings also uncover a zinc-binding motif that is important for NOX5 stability and enzymatic activity, revealing modulation mechanisms of reactive oxygen species (ROS) production.
History
DepositionSep 15, 2023-
Header (metadata) releaseApr 24, 2024-
Map releaseApr 24, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42013.png

Downloads & links

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Map

FileDownload / File: emd_42013.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1.3 Å/pix.
x 240 pix.
= 311.28 Å		1.3 Å/pix.
x 240 pix.
= 311.28 Å		1.3 Å/pix.
x 240 pix.
= 311.28 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.297 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.83
Minimum - Maximum-0.24343455 - 6.8588433
Average (Standard dev.)0.016528217 (±0.088513136)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 311.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #2

Fileemd_42013_additional_1.map
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Additional map: #3

Fileemd_42013_additional_2.map
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Additional map: #4

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Additional map: #1

Fileemd_42013_additional_4.map
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Half map: #1

Fileemd_42013_half_map_1.map
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Half map: #2

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Sample components

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Entire : NADPH oxidase 5

EntireName: NADPH oxidase 5
Components
  • Complex: NADPH oxidase 5
    • Protein or peptide: NADPH oxidase 5
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
  • Ligand: DODECANE
  • Ligand: DECANE
  • Ligand: NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
  • Ligand: HEME B/C
  • Ligand: ZINC ION

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Supramolecule #1: NADPH oxidase 5

SupramoleculeName: NADPH oxidase 5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: NADPH oxidase 5

MacromoleculeName: NADPH oxidase 5 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
EC number: Oxidoreductases; Acting on NADH or NADPH; With oxygen as acceptor
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 82.118992 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSAEEDARWL RWVTQQFKTI AGEDGEISLQ EFKAALHVKE SFFAERFFAL FDSDRSGTIT LQELQEALTL LIHGSPMDKL KFLFQVYDI DGSGSIDPDE LRTVLQSCLR ESAISLPDEK LDQLTLALFE SADADGNGAI TFEELRDELQ RFPGVMENLT I SAAHWLTA ...String:
MSAEEDARWL RWVTQQFKTI AGEDGEISLQ EFKAALHVKE SFFAERFFAL FDSDRSGTIT LQELQEALTL LIHGSPMDKL KFLFQVYDI DGSGSIDPDE LRTVLQSCLR ESAISLPDEK LDQLTLALFE SADADGNGAI TFEELRDELQ RFPGVMENLT I SAAHWLTA PAPRPRPRRP RQLTRAYWHN HRSQLFCLAT YAGLHVLLFG LAASAHRDLG ASVMVAKGCG QCLNFDCSFI AV LMLRRCL TWLRATWLAQ VLPLDQNIQF HQLMGYVVVG LSLVHTVAHT VNFVLQAQAE ASPFQFWELL LTTRPGIGWV HGS ASPTGV ALLLLLLLMF ICSSSCIRRS GHFEVFYWTH LSYLLVWLLL IFHGPNFWKW LLVPGILFFL EKAIGLAVSR MAAV CIMEV NLLPSKVTHL LIKRPPFFHY RPGDYLYLNI PTIARYEWHP FTISSAPEQK DTIWLHIRSQ GQWTNRLYES FKASD PLGR GSKRLSRSVT MRKSQRSSKG SEILLEKHKF CNIKCYIDGP YGTPTRRIFA SEHAVLIGAG IGITPFASIL QSIMYR HQK RKHTCPSCQH SWIEGVQDNM KLHKVDFIWI NRDQRSFEWF VSLLTKLEMD QAEEAQYGRF LELHMYMTSA LGKNDMK AI GLQMALDLLA NKEKKDSITG LQTRTQPGRP DWSKVFQKVA AEKKGKVQVF FCGSPALAKV LKGHCEKFGF RFFQENF

UniProtKB: NADPH oxidase 5

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Macromolecule #2: FLAVIN-ADENINE DINUCLEOTIDE

MacromoleculeName: FLAVIN-ADENINE DINUCLEOTIDE / type: ligand / ID: 2 / Number of copies: 2 / Formula: FAD
Molecular weightTheoretical: 785.55 Da
Chemical component information

ChemComp-FAD:
FLAVIN-ADENINE DINUCLEOTIDE / FAD*YM

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Macromolecule #3: DODECANE

MacromoleculeName: DODECANE / type: ligand / ID: 3 / Number of copies: 2 / Formula: D12
Molecular weightTheoretical: 170.335 Da
Chemical component information

ChemComp-D12:
DODECANE

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Macromolecule #4: DECANE

MacromoleculeName: DECANE / type: ligand / ID: 4 / Number of copies: 2 / Formula: D10
Molecular weightTheoretical: 142.282 Da
Chemical component information

ChemComp-D10:
DECANE

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Macromolecule #5: NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

MacromoleculeName: NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / type: ligand / ID: 5 / Number of copies: 2 / Formula: NAP
Molecular weightTheoretical: 743.405 Da
Chemical component information

ChemComp-NAP:
NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

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Macromolecule #6: HEME B/C

MacromoleculeName: HEME B/C / type: ligand / ID: 6 / Number of copies: 4 / Formula: HEB
Molecular weightTheoretical: 618.503 Da
Chemical component information

ChemComp-HEB:
HEME B/C

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Macromolecule #7: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 7 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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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

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.06 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 220000
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: ANGULAR RECONSTITUTION

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