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- EMDB-40857: Cryo-EM map of cytochrome P450 reductase -

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Basic information

Entry
Database: EMDB / ID: EMD-40857
TitleCryo-EM map of cytochrome P450 reductase
Map data
Sample
  • Complex: Cytochrome P450 reductase
    • Other: Cytochrome P450 reductase
Keywordscytochrome P450 reductase / CPR / POR / electron transfer / endoplasmic reticulum / flavoprotein / oxidoreductase
Function / homology
Function and homology information


iron-cytochrome-c reductase activity / positive regulation of growth plate cartilage chondrocyte proliferation / positive regulation of steroid hormone biosynthetic process / nitrate catabolic process / demethylation / organofluorine metabolic process / carnitine metabolic process / flavonoid metabolic process / nitric oxide dioxygenase NAD(P)H activity / cellular response to gonadotropin stimulus ...iron-cytochrome-c reductase activity / positive regulation of growth plate cartilage chondrocyte proliferation / positive regulation of steroid hormone biosynthetic process / nitrate catabolic process / demethylation / organofluorine metabolic process / carnitine metabolic process / flavonoid metabolic process / nitric oxide dioxygenase NAD(P)H activity / cellular response to gonadotropin stimulus / nitric oxide catabolic process / cytochrome-b5 reductase activity, acting on NAD(P)H / positive regulation of chondrocyte differentiation / cellular response to follicle-stimulating hormone stimulus / NADPH-hemoprotein reductase / NADPH-hemoprotein reductase activity / positive regulation of smoothened signaling pathway / cellular response to peptide hormone stimulus / response to dexamethasone / fatty acid oxidation / response to hormone / nitric oxide biosynthetic process / response to nutrient / electron transport chain / FMN binding / NADP binding / flavin adenine dinucleotide binding / electron transfer activity / oxidoreductase activity / response to xenobiotic stimulus / intracellular membrane-bounded organelle / hydrolase activity / endoplasmic reticulum membrane / negative regulation of apoptotic process / enzyme binding / cytosol
Similarity search - Function
NADPH-cytochrome P450 reductase / Sulfite reductase [NADPH] flavoprotein alpha-component-like, FAD-binding / NADPH-cytochrome p450 reductase, FAD-binding, alpha-helical domain superfamily / FAD binding domain / Flavodoxin-like / Flavoprotein pyridine nucleotide cytochrome reductase / Flavodoxin / Flavodoxin-like domain profile. / Flavodoxin/nitric oxide synthase / Oxidoreductase FAD/NAD(P)-binding ...NADPH-cytochrome P450 reductase / Sulfite reductase [NADPH] flavoprotein alpha-component-like, FAD-binding / NADPH-cytochrome p450 reductase, FAD-binding, alpha-helical domain superfamily / FAD binding domain / Flavodoxin-like / Flavoprotein pyridine nucleotide cytochrome reductase / Flavodoxin / Flavodoxin-like domain profile. / Flavodoxin/nitric oxide synthase / Oxidoreductase FAD/NAD(P)-binding / Oxidoreductase NAD-binding domain / 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 / Flavoprotein-like superfamily
Similarity search - Domain/homology
NADPH--cytochrome P450 reductase
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.33 Å
AuthorsLepesheva GI / Ren Y
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM151876 United States
CitationJournal: Protein Sci / Year: 2026
Title: Cryo-EM reveals an ensemble of cytochrome P450 reductase conformations in solution.
Authors: Galina I Lepesheva / Tatiana Y Hargrove / Yi Ren /
Abstract: The eukaryotic electron transport system, mediated by cytochrome P450 reductase (CPR), plays a crucial role in driving myriads of reactions involved in the biosynthesis of physiologically active ...The eukaryotic electron transport system, mediated by cytochrome P450 reductase (CPR), plays a crucial role in driving myriads of reactions involved in the biosynthesis of physiologically active compounds (such as sterols, steroids, vitamins, and natural products), as well as in the metabolism of drugs, toxins, and carcinogens. CPR is a diflavin-containing enzyme found ubiquitously on the cytosolic side of the endoplasmic reticulum. While several crystal structures of CPR are available, its conformational states in solution, along with the molecular details of action, remain debatable. Here, we determined the 3.3 Å cryo-EM structure of rat CPR, marking the first electron microscopy structure of this relatively small protein (77 kDa). In this structure, the full-length, fully active enzyme adopts a compact conformation, which, however, is more relaxed than in crystal structures. Moreover, we structurally characterized less populated variations of compact CPR conformations and identified a fraction of molecules (~20%) with the FMN-binding domain either not visible or positioned far from the rest of the catalytic core. These results support the idea that large-scale interdomain rearrangements serve as the structural basis for CPR function and suggest that cryo-EM techniques can help uncover the intricate molecular mechanisms governing the CPR-mediated electron transfer cycle.
History
DepositionMay 23, 2023-
Header (metadata) releaseDec 4, 2024-
Map releaseDec 4, 2024-
UpdateFeb 4, 2026-
Current statusFeb 4, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40857.png

Downloads & links

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Map

FileDownload / File: emd_40857.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 256 pix.
= 165.632 Å		0.65 Å/pix.
x 256 pix.
= 165.632 Å		0.65 Å/pix.
x 256 pix.
= 165.632 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.647 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.33160114 - 0.5195663
Average (Standard dev.)0.00043374486 (±0.015168365)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 165.632 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_40857_msk_1.map
Projections & Slices
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Additional map: #1

Fileemd_40857_additional_1.map
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Half map: #2

Fileemd_40857_half_map_1.map
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Half map: #1

Fileemd_40857_half_map_2.map
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Sample components

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Entire : Cytochrome P450 reductase

EntireName: Cytochrome P450 reductase
Components
  • Complex: Cytochrome P450 reductase
    • Other: Cytochrome P450 reductase

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Supramolecule #1: Cytochrome P450 reductase

SupramoleculeName: Cytochrome P450 reductase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 78 KDa

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Macromolecule #1: Cytochrome P450 reductase

MacromoleculeName: Cytochrome P450 reductase / type: other / ID: 1 / Classification: other
Source (natural)Organism: Rattus norvegicus (Norway rat)
SequenceString: MGDSHEDTSA TMPEAVAEEV SLFSTTDMVL FSLIVGVLTY WFIFRKKKEE IPEFSKIQTT APPVKESSFV EKMKKTGRNI IVFYGSQTGT AEEFANRLSK DAHRYGMRGM SADPEEYDLA DLSSLPEIDK SLVVFCMATY GEGDPTDNAQ DFYDWLQETD VDLTGVKFAV ...String:
MGDSHEDTSA TMPEAVAEEV SLFSTTDMVL FSLIVGVLTY WFIFRKKKEE IPEFSKIQTT APPVKESSFV EKMKKTGRNI IVFYGSQTGT AEEFANRLSK DAHRYGMRGM SADPEEYDLA DLSSLPEIDK SLVVFCMATY GEGDPTDNAQ DFYDWLQETD VDLTGVKFAV FGLGNKTYEH FNAMGKYVDQ RLEQLGAQRI FELGLGDDDG NLEEDFITWR EQFWPAVCEF FGVEATGEES SIRQYELVVH EDMDVAKVYT GEMGRLKSYE NQKPPFDAKN PFLAAVTANR KLNQGTERHL MHLELDISDS KIRYESGDHV AVYPANDSAL VNQIGEILGA DLDVIMSLNN LDEESNKKHP FPCPTTYRTA LTYYLDITNP PRTNVLYELA QYASEPSEQE HLHKMASSSG EGKELYLSWV VEARRHILAI LQDYPSLRPP IDHLCELLPR LQARYYSIAS SSKVHPNSVH ICAVAVEYEA KSGRVNKGVA TSWLRAKEPA GENGGRALVP MFVRKSQFRL PFKSTTPVIM VGPGTGIAPF MGFIQERAWL REQGKEVGET LLYYGCRRSD EDYLYREELA RFHKDGALTQ LNVAFSREQA HKVYVQHLLK RDREHLWKLI HEGGAHIYVC GDARNMAKDV QNTFYDIVAE FGPMEHTQAV DYVKKLMTKG RYSLDVWS

GENBANK: GENBANK: NP_113764
Recombinant expressionOrganism: Escherichia coli (E. coli)

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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

Concentration0.23 mg/mL
BufferpH: 7.4 / Details: PBS
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
TemperatureMin: 77.0 K / Max: 77.0 K
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 1 / Number real images: 31000 / Average exposure time: 0.899 sec. / Average electron dose: 53.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: OTHER / Imaging mode: OTHER / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 130000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 30000000
CTF correctionType: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

3es9

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.33 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 671545
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
Final 3D classificationNumber classes: 50 / Software - Name: cryoSPARC (ver. 4.6)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL / Overall B value: 181
Output model

PDB-9ef0:
EM structure of cytochrome P450 reductase

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