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- EMDB-48544: Structure of mycobacterial NDH2 (type II NADH:quinone oxidoreductase) -

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Basic information

Entry
Database: EMDB / ID: EMD-48544
TitleStructure of mycobacterial NDH2 (type II NADH:quinone oxidoreductase)
Map data
Sample
  • Complex: NDH2 (non-electrogenic NADH:quinone oxidoreductase) from Mycobacterium smegmatis
    • Protein or peptide: NADH:ubiquinone reductase (non-electrogenic)
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
Keywordsflavoprotein / oxidoreductase / electron transport / metabolism / MEMBRANE PROTEIN
Function / homologyAlternative NADH dehydrogenase / NADH:quinone reductase (non-electrogenic) / : / NADH dehydrogenase (quinone) (non-electrogenic) activity / FAD/NAD(P)-binding domain / Pyridine nucleotide-disulphide oxidoreductase / FAD/NAD(P)-binding domain superfamily / membrane / NADH:ubiquinone reductase (non-electrogenic)
Function and homology information
Biological speciesMycolicibacterium smegmatis MC2 155 (bacteria)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsLiang Y / Rubinstein JL
Funding support Canada, 1 items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)PJT191893 Canada
CitationJournal: J Med Chem / Year: 2025
Title: Structure of Mycobacterial NDH-2 Bound to a 2-Mercapto-Quinazolinone Inhibitor.
Authors: Yingke Liang / Stephanie A Bueler / Gregory M Cook / John L Rubinstein /
Abstract: Mycobacterial type II NADH dehydrogenase (NDH-2) is a promising drug target because of its central role in energy metabolism in and other pathogens, and because it lacks a known mammalian homologue. ...Mycobacterial type II NADH dehydrogenase (NDH-2) is a promising drug target because of its central role in energy metabolism in and other pathogens, and because it lacks a known mammalian homologue. To facilitate optimization of lead compounds, we used electron cryomicroscopy (cryo-EM) to determine the structure of NDH-2 from , a fast-growing nonpathogenic model for respiration in . The structure shows that active mycobacterial NDH-2 is dimeric, with an arrangement of monomers in the dimer that differs from the arrangement described for other prokaryotic NDH-2 dimers, instead resembling dimers formed by NDH-2 in the eukaryotes and . A structure of the enzyme bound to a 2-mercapto-quinazolinone inhibitor shows that the compound interacts directly with the flavin adenine dinucleotide cofactor, blocking the menaquinone-reducing site. These results reveal structural elements of NDH-2 that could be used to design specific inhibitors of the mycobacterial enzyme.
History
DepositionJan 6, 2025-
Header (metadata) releaseJan 22, 2025-
Map releaseJan 22, 2025-
UpdateMay 21, 2025-
Current statusMay 21, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48544.png

Downloads & links

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Map

FileDownload / File: emd_48544.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.64 Å/pix.
x 384 pix.
= 245.76 Å		0.64 Å/pix.
x 384 pix.
= 245.76 Å		0.64 Å/pix.
x 384 pix.
= 245.76 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.64 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.045
Minimum - Maximum-0.17339326 - 0.3336999
Average (Standard dev.)0.00044043988 (±0.007883918)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 245.76 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_48544_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_48544_half_map_2.map
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Sample components

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Entire : NDH2 (non-electrogenic NADH:quinone oxidoreductase) from Mycobact...

EntireName: NDH2 (non-electrogenic NADH:quinone oxidoreductase) from Mycobacterium smegmatis
Components
  • Complex: NDH2 (non-electrogenic NADH:quinone oxidoreductase) from Mycobacterium smegmatis
    • Protein or peptide: NADH:ubiquinone reductase (non-electrogenic)
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE

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Supramolecule #1: NDH2 (non-electrogenic NADH:quinone oxidoreductase) from Mycobact...

SupramoleculeName: NDH2 (non-electrogenic NADH:quinone oxidoreductase) from Mycobacterium smegmatis
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Homodimer composed of two monomers of NDH2 from Mycobacterium smegmatis.
Source (natural)Organism: Mycolicibacterium smegmatis MC2 155 (bacteria) / Synthetically produced: Yes
Molecular weightTheoretical: 49 KDa

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Macromolecule #1: NADH:ubiquinone reductase (non-electrogenic)

MacromoleculeName: NADH:ubiquinone reductase (non-electrogenic) / type: protein_or_peptide / ID: 1
Details: Includes sequence for a linker followed by a 3xFLAG affinity tag at the C terminus,Includes sequence for a linker followed by a 3xFLAG affinity tag at the C terminus
Number of copies: 2 / Enantiomer: LEVO / EC number: NADH:quinone reductase (non-electrogenic)
Source (natural)Organism: Mycolicibacterium smegmatis MC2 155 (bacteria)
Molecular weightTheoretical: 53.14532 KDa
SequenceString: MSHPGATASD RHKVVIIGSG FGGLTAAKTL KRADVDVKLI ARTTHHLFQP LLYQVATGII SEGEIAPATR VILRKQKNAQ VLLGDVTHI DLENKTVDSV LLGHTYSTPY DSLIIAAGAG QSYFGNDHFA EFAPGMKSID DALELRGRIL GAFEQAERSS D PVRRAKLL ...String:
MSHPGATASD RHKVVIIGSG FGGLTAAKTL KRADVDVKLI ARTTHHLFQP LLYQVATGII SEGEIAPATR VILRKQKNAQ VLLGDVTHI DLENKTVDSV LLGHTYSTPY DSLIIAAGAG QSYFGNDHFA EFAPGMKSID DALELRGRIL GAFEQAERSS D PVRRAKLL TFTVVGAGPT GVEMAGQIAE LADQTLRGSF RHIDPTEARV ILLDAAPAVL PPMGEKLGKK ARARLEKMGV EV QLGAMVT DVDRNGITVK DSDGTIRRIE SACKVWSAGV SASPLGKDLA EQSGVELDRA GRVKVQPDLT LPGHPNVFVV GDM AAVEGV PGVAQGAIQG GRYAAKIIKR EVSGTSPKIR TPFEYFDKGS MATVSRFSAV AKVGPVEFAG FFAWLCWLVL HLVY LVGFK TKIVTLLSWG VTFLSTKRGQ LTITEQQAYA RTRIEELEEI AAAVQDTEKA ASGLSGQPPR SPSSGSSDYK DHDGD YKDH DIDYKDDDDK

UniProtKB: NADH:ubiquinone reductase (non-electrogenic)

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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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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 6.8
GridModel: Homemade / Material: COPPER/RHODIUM / Mesh: 400 / Support film - Material: GOLD / Support film - topology: HOLEY / Support film - Film thickness: 35 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 15 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 120000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.6.2) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Details: Initial map was generated ab initio in cryoSPARC v4.6.2
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.2) / Number images used: 59561
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2)
FSC plot (resolution estimation)

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