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- EMDB-43417: Focused map of the condensing region of hFASN/NADPH State 1 -

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Basic information

Entry
Database: EMDB / ID: EMD-43417
TitleFocused map of the condensing region of hFASN/NADPH State 1
Map dataFocused map of the condensing region of hFASN/NADPH State 1
Sample
  • Complex: human Fatty Acid Synthase
KeywordsMegasynthase / Lipogenesis / BIOSYNTHETIC PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.27 Å
AuthorsSchultz K / Marmorstein R
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM118090 United States
CitationJournal: Nature / Year: 2025
Title: Snapshots of acyl carrier protein shuttling in human fatty acid synthase.
Authors: Kollin Schultz / Pedro Costa-Pinheiro / Lauren Gardner / Laura V Pinheiro / Julio Ramirez-Solis / Sarah M Gardner / Kathryn E Wellen / Ronen Marmorstein /
Abstract: The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, a single gene encodes six catalytically active domains and a flexibly ...The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, a single gene encodes six catalytically active domains and a flexibly tethered acyl carrier protein (ACP) domain that shuttles intermediates between active sites for fatty acid biosynthesis. FASN is an essential enzyme in mammalian development through the role that fatty acids have in membrane formation, energy storage, cell signalling and protein modifications. Thus, FASN is a promising target for treatment of a large variety of diseases including cancer, metabolic dysfunction-associated fatty liver disease, and viral and parasite infections. The multi-faceted mechanism of FASN and the dynamic nature of the protein, in particular of the ACP, have made it challenging to understand at the molecular level. Here we report cryo-electron microscopy structures of human FASN in a multitude of conformational states with NADPH and NADP plus acetoacetyl-CoA present, including structures with the ACP stalled at the dehydratase (DH) and enoyl-reductase (ER) domains. We show that FASN activity in vitro and de novo lipogenesis in cells is inhibited by mutations at the ACP-DH and ACP-ER interfaces. Together, these studies provide new molecular insights into the dynamic nature of FASN and the ACP shuttling mechanism, with implications for developing improved FASN-targeted therapeutics.
History
DepositionJan 16, 2024-
Header (metadata) releaseFeb 26, 2025-
Map releaseFeb 26, 2025-
UpdateMar 5, 2025-
Current statusMar 5, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43417.png

Downloads & links

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Map

FileDownload / File: emd_43417.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFocused map of the condensing region of hFASN/NADPH State 1
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 360 pix.
= 384.84 Å		1.07 Å/pix.
x 360 pix.
= 384.84 Å		1.07 Å/pix.
x 360 pix.
= 384.84 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.069 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.204
Minimum - Maximum-0.16900045 - 0.73510635
Average (Standard dev.)0.00061408343 (±0.018181393)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 384.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_43417_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map b

Fileemd_43417_half_map_1.map
AnnotationHalf map b
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map a

Fileemd_43417_half_map_2.map
AnnotationHalf map a
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human Fatty Acid Synthase

EntireName: human Fatty Acid Synthase
Components
  • Complex: human Fatty Acid Synthase

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Supramolecule #1: human Fatty Acid Synthase

SupramoleculeName: human Fatty Acid Synthase / type: complex / ID: 1 / Parent: 0
Details: Focused map of the condensing region of human FASN with NADPH in State 1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 554 KDa

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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

Concentration3.5 mg/mL
BufferpH: 7
GridModel: Quantifoil R0.6/1 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Slit width: 30 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 5760 pixel / Digitization - Dimensions - Height: 4092 pixel / Number grids imaged: 2 / Number real images: 19126 / Average electron dose: 52.4 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.27 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4) / Number images used: 130804
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC
FSC plot (resolution estimation)

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