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- PDB-8ys6: Helicobacter pylori OorDABC in complex with Napabucasin -

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Basic information

Entry
Database: PDB / ID: 8ys6
TitleHelicobacter pylori OorDABC in complex with Napabucasin
Components
  • (2-oxoglutarate ...) x 2
  • (2-oxoglutarate:acceptor ...) x 2
KeywordsOXIDOREDUCTASE / Oxoglutarate Oxidoreductase / Electron Transport / Tricarboxylic Acid Cycle / Napabucasin
Function / homology
Function and homology information


2-oxoglutarate synthase activity / small molecule metabolic process / thiamine pyrophosphate binding
Similarity search - Function
: / Thiamine pyrophosphate enzyme, C-terminal TPP-binding / Thiamine pyrophosphate enzyme, C-terminal TPP binding domain / Thiamin diphosphate-binding fold
Similarity search - Domain/homology
: / IRON/SULFUR CLUSTER / THIAMINE DIPHOSPHATE / 2-oxoglutarate ferredoxin oxidoreductase subunit beta / : / : / :
Similarity search - Component
Biological speciesHelicobacter pylori (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsLan, W. / Gao, Y. / Bi, H.
Funding support China, 7items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82073899 China
National Natural Science Foundation of China (NSFC)31570053 China
National Natural Science Foundation of China (NSFC)31870029 China
National Natural Science Foundation of China (NSFC)82302542 China
The National Key Research and Development Program of China2018YFC0311003
The National Key Research and Development Program of China2022YFA1305900
Shanghai Rising-Star Program23QA1406400
CitationJournal: Nat Commun / Year: 2025
Title: 2-oxoglutarate:acceptor oxidoreductase-catalyzed redox cycling effectively targets coccoid forms of Helicobacter pylori.
Authors: Xudong Hang / Weiqi Lan / Huang Yanqiang / Hongming Huang / Mingjing Zhang / Liping Zeng / Ting Shi / Yuefan Bai / Zhiyu Yang / Shanwei Hu / Junfan Wang / Linlin Dong / Qian Tong / Jia Jia / ...Authors: Xudong Hang / Weiqi Lan / Huang Yanqiang / Hongming Huang / Mingjing Zhang / Liping Zeng / Ting Shi / Yuefan Bai / Zhiyu Yang / Shanwei Hu / Junfan Wang / Linlin Dong / Qian Tong / Jia Jia / Shuzhuang Bi / Qianfeng Xia / Yan Gao / Hongkai Bi /
Abstract: Helicobacter pylori, a globally significant pathogen, plays a central etiological role in diverse gastric pathologies ranging from chronic gastritis and peptic ulcers to gastric adenocarcinoma. ...Helicobacter pylori, a globally significant pathogen, plays a central etiological role in diverse gastric pathologies ranging from chronic gastritis and peptic ulcers to gastric adenocarcinoma. Although conventional antibiotics effectively inhibit or kill growing helical H. pylori, metabolically dormant coccoid forms of H. pylori exhibit considerable tolerance, posing a persistent and clinically significant challenge. Here, we report napabucasin (2-acetylfuro-1,4-naphthoquinone) as a redox-cycling antibiotic with potent bactericidal activity against both drug-resistant helical and coccoid forms of H. pylori. Notably, napabucasin does not induce acquired resistance in vitro and demonstrates superior efficacy compared to standard triple therapy in murine infection models. Mechanistic studies reveal that napabucasin acts through 2-oxoglutarate:acceptor oxidoreductase (OOR)-catalyzed futile redox cycling, generating bactericidal levels of reactive oxygen species (ROS). Compared to menaquinone 6, a proposed physiological electron acceptor, napabucasin exhibits enhanced oxidative capacity. Structural, biochemical, and microbiological analyses identify Leu44 and Lys46 within the OorD subunit as critical residues for napabucasin recognition and catalysis. These findings establish OOR-mediated redox cycling as a robust antimicrobial strategy that sustains endogenous ROS production to combat refractory H. pylori infections.
History
DepositionMar 22, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jul 2, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: 2-oxoglutarate:acceptor oxidoreductase
A: 2-oxoglutarate synthase subunit alpha
C: 2-oxoglutarate ferredoxin oxidoreductase subunit beta
B: 2-oxoglutarate:acceptor oxidoreductase
F: 2-oxoglutarate:acceptor oxidoreductase
G: 2-oxoglutarate synthase subunit alpha
H: 2-oxoglutarate ferredoxin oxidoreductase subunit beta
I: 2-oxoglutarate:acceptor oxidoreductase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)213,02720
Polymers209,5378
Non-polymers3,48912
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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2-oxoglutarate:acceptor ... , 2 types, 4 molecules DFBI

#1: Protein 2-oxoglutarate:acceptor oxidoreductase / 2-oxoglutarate oxidoreductase OorD subunit / 4Fe-4S dicluster domain-containing protein


Mass: 12467.625 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Helicobacter pylori (bacteria)
Gene: AM496_04450, BB411_07145, C2R64_04560, D8X81_03145, DD775_02535, EC515_04135, EC541_05865, EC589_03065, HPY1198_04840, HPY1846_01345
Production host: Escherichia coli (E. coli) / References: UniProt: A0A0B2EGL0
#4: Protein 2-oxoglutarate:acceptor oxidoreductase / 2-oxoglutarate oxidoreductase OorC subunit


Mass: 20253.453 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Helicobacter pylori (bacteria)
Gene: oorC, C2R64_04575, C2S01_06595, EC570_04720, ECC29_01410, ECC33_03045
Production host: Escherichia coli (E. coli) / References: UniProt: A0A0B2EEZ8

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2-oxoglutarate ... , 2 types, 4 molecules AGCH

#2: Protein 2-oxoglutarate synthase subunit alpha


Mass: 41565.902 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Helicobacter pylori (bacteria) / Gene: C2R48_00275 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A2T6W5S4
#3: Protein 2-oxoglutarate ferredoxin oxidoreductase subunit beta / 2-oxoglutarate oxidoreductase subunit KorB / 2-oxoglutarate-acceptor oxidoreductase subunit OorB


Mass: 30481.701 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Helicobacter pylori (bacteria)
Gene: oorB, korB, AM497_01150, AM498_01330, B0X30_00560, B0X44_00010, B0X50_03675, B0X54_05595, B0X62_02935, BB411_07135, BB413_05640, BB424_05915, BB459_03745, BB461_04720, BB464_04365, BB477_04855, ...Gene: oorB, korB, AM497_01150, AM498_01330, B0X30_00560, B0X44_00010, B0X50_03675, B0X54_05595, B0X62_02935, BB411_07135, BB413_05640, BB424_05915, BB459_03745, BB461_04720, BB464_04365, BB477_04855, BB479_06520, BGL55_07715, BGL66_00450, BGL68_05120, BGL69_01465, BGL72_06170, BXP09_03780, C2840_03070, C2R45_06185, C2R60_07105, C2R62_02105, C2R64_04570, C2R66_01600, C2R71_01550, C2R81_00990, C2R85_07970, C2R86_01670, C2R96_02100, C2S01_06600, C2S04_03540, C2S07_06030, C2S08_01675, C2S19_05560, C2S26_01775, C2S41_04370, C2S43_01830, C2S44_08445, CV723_03795, CV726_04550, CV728_03440, CV729_03960, CV730_03830, D2C73_05440, D2C76_08055, D2C79_04285, D2C84_02640, D2C85_05055, D2C87_02355, D8X56_03120, D8X81_03155, DD750_02510, DD754_03015, DD756_02785, DD764_03055, DD775_02545, DD794_03540, DDP37_03580, DDP42_03140, DDP57_02985, EC508_04845, EC515_04145, EC518_06710, EC525_03565, EC532_06000, EC533_02415, EC535_02670, EC538_03525, EC547_02955, EC551_04645, EC553_02910, EC556_02780, EC568_02905, EC569_04000, EC570_04715, EC572_05350, EC574_04050, EC582_05020, EC589_03055, EC595_02590, EC597_01970, EC598_00990, EC600_00880, EC601_02710, ECB88_05740, ECB91_01840, ECC09_04670, ECC11_04890, ECC12_01920, ECC19_03410, ECC24_01145, ECC25_02460, ECC26_02695, ECC33_03050, ECC34_02995, ECC35_03455, ECC43_04085, ECC49_04355, ECE46_02140, EDB75_01155, EDC85_02050, EGW01_04140, EPC67_05165, EPC72_01580, EPC80_01190, F7187_05770, F7198_05900, F7221_03625, F7229_07365, HPPMSS1_c00647, HPY1198_04850, NCTC12823_00718
Production host: Escherichia coli (E. coli) / References: UniProt: A0A024BZG2, 2-oxoglutarate synthase

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Non-polymers , 4 types, 12 molecules

#5: Chemical
ChemComp-SF4 / IRON/SULFUR CLUSTER


Mass: 351.640 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Fe4S4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-A1D65 / Napabucasin


Mass: 240.211 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H8O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical ChemComp-TPP / THIAMINE DIPHOSPHATE


Mass: 425.314 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H19N4O7P2S / Feature type: SUBJECT OF INVESTIGATION

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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: Helicobacter pylori OorDABC in complex with Napabucasin
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Helicobacter pylori (bacteria)
Source (recombinant)Organism: Escherichia coli (E. coli)
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 146076 / Symmetry type: POINT

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