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- EMDB-60311: Cryo-EM map of respirasome closed state 1 bound by metformin (SC-... -

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Basic information

Entry
Database: EMDB / ID: EMD-60311
TitleCryo-EM map of respirasome closed state 1 bound by metformin (SC-MetC1), complex III2 focused
Map data
Sample
  • Complex: Respirasome close state 1 in presence of metformin
Keywordsmetformin / electron transport chain / Respirasome / MEMBRANE PROTEIN
Biological speciesSus scrofa (pig)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsTeng F / He ZX / Hu YQ / Xu CY / Guo RY / Zhou L
Funding support1 items
OrganizationGrant numberCountry
Other governmentZJU100 Young Professor
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Hydrophilic metformin and hydrophobic biguanides inhibit mitochondrial complex I by distinct mechanisms.
Authors: Zhaoxiang He / Fei Teng / Yanqing Yang / Ruiyang Guo / Mengchen Wu / Fangzhu Han / Hongtao Tian / Jiawei Wang / Yiqi Hu / Yangwei Jiang / Leili Zhang / Chenyang Xu / Fan Yang / Jiancang Zhou ...Authors: Zhaoxiang He / Fei Teng / Yanqing Yang / Ruiyang Guo / Mengchen Wu / Fangzhu Han / Hongtao Tian / Jiawei Wang / Yiqi Hu / Yangwei Jiang / Leili Zhang / Chenyang Xu / Fan Yang / Jiancang Zhou / Shan Zhang / James A Letts / Ruhong Zhou / Long Zhou /
Abstract: Metformin is the only antihyperglycemic biguanide targeting type 2 diabetes mellitus with proven safety. Although a mechanism of action involving tight inhibition of the respiratory complex I has ...Metformin is the only antihyperglycemic biguanide targeting type 2 diabetes mellitus with proven safety. Although a mechanism of action involving tight inhibition of the respiratory complex I has been proposed for hydrophobic biguanides, it remains elusive for the hydrophilic metformin, whose excellent pharmacological tolerance depends on weak complex I inhibition without competitive nature. Here we solved cryo-electron microscopy structures of the metformin-bound porcine respirasome. Our structural and kinetic data are consistent with a model in which metformin enters complex I only in its open state and becomes trapped at the ubiquinone redox site by ubiquinone-induced conformational closing of the enzyme. By contrast, the hydrophobic proguanil alone occupies both the entrance and the redox site of the ubiquinone channel in open and closed complex I and is kinetically consistent with competitive inhibition with conformation-dependent affinities. Our data provide the molecular basis for metformin's well-known superior properties, such as a wide therapeutic window and positive ubiquinone cooperativity, leading to its clinical success and facilitating future therapeutic developments.
History
DepositionMay 28, 2024-
Header (metadata) releaseNov 19, 2025-
Map releaseNov 19, 2025-
UpdateNov 19, 2025-
Current statusNov 19, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_60311.png

Downloads & links

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Map

FileDownload / File: emd_60311.map.gz / Format: CCP4 / Size: 421.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
1.2 Å/pix.
x 480 pix.
= 576. Å		1.2 Å/pix.
x 480 pix.
= 576. Å		1.2 Å/pix.
x 480 pix.
= 576. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.2 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.4
Minimum - Maximum-6.401292 - 11.245813999999999
Average (Standard dev.)-0.0027979058 (±0.2211068)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions480480480
Spacing480480480
CellA=B=C: 576.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_60311_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

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Half map: #1

Fileemd_60311_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_60311_half_map_2.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Respirasome close state 1 in presence of metformin

EntireName: Respirasome close state 1 in presence of metformin
Components
  • Complex: Respirasome close state 1 in presence of metformin

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Supramolecule #1: Respirasome close state 1 in presence of metformin

SupramoleculeName: Respirasome close state 1 in presence of metformin / type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Sus scrofa (pig)

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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

Concentration0.25 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMTrisTrimethylsilyl
50.0 mMNaClSodium chloride
0.002 %PMSFPhenylmethylsulfonyl
0.1 %GDNGlyco-diosgenin

Details: SEC buffer (20 mM Tris pH 7.4, 50 mM NaCl, 0.002% PMSF, 0.1% GDN (w/v))
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: CONTINUOUS / Support film - Film thickness: 2
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Digitization - Dimensions - Width: 4096 pixel / Digitization - Dimensions - Height: 4096 pixel / Number grids imaged: 1 / Average exposure time: 7.8 sec. / Average electron dose: 51.9 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: CTFFIND (ver. 4.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v.3.3.2) / Number images used: 320129
Initial angle assignmentType: COMMON LINE / Software - Name: cryoSPARC (ver. v.3.3.2)
Final angle assignmentType: COMMON LINE / Software - Name: cryoSPARC (ver. v.3.3.2)
Final 3D classificationSoftware - Name: cryoSPARC (ver. v.3.3.2)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT

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