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- PDB-8u86: Structural Basis of Human NOX5 Activation -

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Basic information

Entry
Database: PDB / ID: 8u86
TitleStructural Basis of Human NOX5 Activation
ComponentsNADPH oxidase 5
KeywordsMEMBRANE PROTEIN / enzyme / oxidase / activation mechanism
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
DECANE / DODECANE / FLAVIN-ADENINE DINUCLEOTIDE / HEME B/C / Chem-NDP / NADPH oxidase 5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsCui, C. / Jiang, M. / Sun, J.
Funding support United States, 1items
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2024Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references / Structure summary
Category: audit_author / citation_author / em_author_list
Item: _audit_author.name / _citation_author.name / _em_author_list.author
Revision 1.2Nov 6, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: NADPH oxidase 5
C: NADPH oxidase 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,46515
Polymers164,2382
Non-polymers6,22713
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 2 molecules AC

#1: Protein NADPH oxidase 5


Mass: 82118.992 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NOX5 / Production host: Homo sapiens (human)
References: UniProt: Q96PH1, Oxidoreductases; Acting on NADH or NADPH; With oxygen as acceptor

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Non-polymers , 6 types, 13 molecules

#2: Chemical
ChemComp-HEB / HEME B/C / HYBRID BETWEEN B AND C TYPE HEMES (PROTOPORPHYRIN IX CONTAINING FE)


Mass: 618.503 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H34FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H33N9O15P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: FAD*YM
#5: Chemical ChemComp-D12 / DODECANE


Mass: 170.335 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H26
#6: Chemical ChemComp-D10 / DECANE


Mass: 142.282 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H22
#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: NADPH oxidase 5 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 5000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.20_4459: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 201424 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0067882
ELECTRON MICROSCOPYf_angle_d0.68110774
ELECTRON MICROSCOPYf_dihedral_angle_d23.5482712
ELECTRON MICROSCOPYf_chiral_restr0.0461126
ELECTRON MICROSCOPYf_plane_restr0.0041280

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