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- EMDB-43350: Composite structure of human FASN with NADPH in State 4 -

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Basic information

Entry
Database: EMDB / ID: EMD-43350
TitleComposite structure of human FASN with NADPH in State 4
Map dataComposite map of hFASN/NADPH State 4
Sample
  • Complex: human Fatty Acid Synthase
    • Protein or peptide: Fatty acid synthase
  • Ligand: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
KeywordsMegasynthase / Lipogenesis / BIOSYNTHETIC PROTEIN
Function / homology
Function and homology information


fatty-acid synthase system / ether lipid biosynthetic process / Vitamin B5 (pantothenate) metabolism / neutrophil differentiation / fatty-acyl-CoA biosynthetic process / enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific) / glandular epithelial cell development / establishment of endothelial intestinal barrier / [acyl-carrier-protein] S-acetyltransferase / [acyl-carrier-protein] S-acetyltransferase activity ...fatty-acid synthase system / ether lipid biosynthetic process / Vitamin B5 (pantothenate) metabolism / neutrophil differentiation / fatty-acyl-CoA biosynthetic process / enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific) / glandular epithelial cell development / establishment of endothelial intestinal barrier / [acyl-carrier-protein] S-acetyltransferase / [acyl-carrier-protein] S-acetyltransferase activity / glycogen granule / Fatty acyl-CoA biosynthesis / oleoyl-[acyl-carrier-protein] hydrolase / fatty acyl-[ACP] hydrolase activity / modulation by host of viral process / ChREBP activates metabolic gene expression / [acyl-carrier-protein] S-malonyltransferase / 3-hydroxyacyl-[acyl-carrier-protein] dehydratase / enoyl-[acyl-carrier-protein] reductase (NADPH) activity / [acyl-carrier-protein] S-malonyltransferase activity / beta-ketoacyl-[acyl-carrier-protein] synthase I / (3R)-hydroxyacyl-[acyl-carrier-protein] dehydratase activity / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / mammary gland development / 3-oxoacyl-[acyl-carrier-protein] reductase / 3-oxoacyl-[acyl-carrier-protein] reductase (NADPH) activity / fatty acid synthase activity / monocyte differentiation / phosphopantetheine binding / 3-oxoacyl-[acyl-carrier-protein] synthase activity / cellular response to interleukin-4 / Activation of gene expression by SREBF (SREBP) / fatty acid metabolic process / fatty acid biosynthetic process / osteoblast differentiation / melanosome / cadherin binding / inflammatory response / Golgi apparatus / RNA binding / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
: / Fatty acid synthase, pseudo-KR domain / Methyltransferase type 12 / Methyltransferase domain / Thioesterase / Thioesterase domain / Polyketide synthase, dehydratase domain / PKS_DH / : / Polyketide synthase dehydratase domain ...: / Fatty acid synthase, pseudo-KR domain / Methyltransferase type 12 / Methyltransferase domain / Thioesterase / Thioesterase domain / Polyketide synthase, dehydratase domain / PKS_DH / : / Polyketide synthase dehydratase domain / Polyketide synthase, dehydratase domain superfamily / : / Polyketide and metazoan fatty acid synthase dehydratase (PKS/mFAS DH) domain profile. / Polyketide synthase, C-terminal extension / Ketoacyl-synthetase C-terminal extension / Polyketide synthase, ketoreductase domain / KR domain / Malonyl-CoA ACP transacylase, ACP-binding / : / Alcohol dehydrogenase-like, C-terminal / Acyl transferase / Acyl transferase domain / Acyl transferase domain in polyketide synthase (PKS) enzymes. / Zinc-binding dehydrogenase / Acyl transferase domain superfamily / Acyl transferase/acyl hydrolase/lysophospholipase / Polyketide synthase, enoylreductase domain / Enoylreductase / Polyketide synthase, phosphopantetheine-binding domain / Phosphopantetheine attachment site / PKS_KR / Beta-ketoacyl synthase, active site / Ketosynthase family 3 (KS3) active site signature. / Beta-ketoacyl synthase / Ketosynthase family 3 (KS3) domain profile. / Beta-ketoacyl synthase, N-terminal / Beta-ketoacyl synthase, C-terminal / Polyketide synthase, beta-ketoacyl synthase domain / Beta-ketoacyl synthase, N-terminal domain / Beta-ketoacyl synthase, C-terminal domain / GroES-like superfamily / Thiolase-like / Phosphopantetheine attachment site / Phosphopantetheine attachment site. / Phosphopantetheine attachment site / ACP-like superfamily / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP domain / Alpha/Beta hydrolase fold / NAD(P)-binding domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 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 12, 2024-
Header (metadata) releaseFeb 26, 2025-
Map releaseFeb 26, 2025-
UpdateMay 14, 2025-
Current statusMay 14, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43350.png

Downloads & links

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Map

FileDownload / File: emd_43350.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite map of hFASN/NADPH State 4
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: 0.182
Minimum - Maximum-0.16851664 - 0.7284264
Average (Standard dev.)0.001499397 (±0.027286278)
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_43350_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Consensus map before focused refinement of hFASN/NADPH State 4

Fileemd_43350_additional_1.map
AnnotationConsensus map before focused refinement of hFASN/NADPH State 4
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Sharpened composite map of hFASN/NADPH State 4

Fileemd_43350_additional_2.map
AnnotationSharpened composite map of hFASN/NADPH State 4
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map a

Fileemd_43350_half_map_1.map
AnnotationHalf map a
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map b

Fileemd_43350_half_map_2.map
AnnotationHalf map b
Projections & Slices
AxesZYX

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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
    • Protein or peptide: Fatty acid synthase
  • Ligand: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

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Supramolecule #1: human Fatty Acid Synthase

SupramoleculeName: human Fatty Acid Synthase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Composite structure of human FASN with NADPH in State 4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 554 KDa

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Macromolecule #1: Fatty acid synthase

MacromoleculeName: Fatty acid synthase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: fatty-acid synthase system
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 278.722219 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYYDYKDDD DKDYDIPTTE NLYFQGAMGS GIPEEVVIAG MSGKLPESEN LQEFWDNLIG GVDMVTDDDR RWKAGLYGLP RRSGKLKDL SRFDASFFGV HPKQAHTMDP QLRLLLEVTY EAIVDGGINP DSLRGTHTGV WVGVSGSETS EALSRDPETL V GYSMVGCQ ...String:
MSYYDYKDDD DKDYDIPTTE NLYFQGAMGS GIPEEVVIAG MSGKLPESEN LQEFWDNLIG GVDMVTDDDR RWKAGLYGLP RRSGKLKDL SRFDASFFGV HPKQAHTMDP QLRLLLEVTY EAIVDGGINP DSLRGTHTGV WVGVSGSETS EALSRDPETL V GYSMVGCQ RAMMANRLSF FFDFRGPSIA LDTACSSSLM ALQNAYQAIH SGQCPAAIVG GINVLLKPNT SVQFLRLGML SP EGTCKAF DTAGNGYCRS EGVVAVLLTK KSLARRVYAT ILNAGTNTDG FKEQGVTFPS GDIQEQLIRS LYQSAGVAPE SFE YIEAHG TGTKVGDPQE LNGITRALCA TRQEPLLIGS TKSNMGHPEP ASGLAALAKV LLSLEHGLWA PNLHFHSPNP EIPA LLDGR LQVVDQPLPV RGGNVGINSF GFGGSNVHII LRPNTQPPPA PAPHATLPRL LRASGRTPEA VQKLLEQGLR HSQDL AFLS MLNDIAAVPA TAMPFRGYAV LGGERGGPEV QQVPAGERPL WFICSGMGTQ WRGMGLSLMR LDRFRDSILR SDEAVK PFG LKVSQLLLST DESTFDDIVH SFVSLTAIQI GLIDLLSCMG LRPDGIVGHS LGEVACGYAD GCLSQEEAVL AAYWRGQ CI KEAHLPPGAM AAVGLSWEEC KQRCPPGVVP ACHNSKDTVT ISGPQAPVFE FVEQLRKEGV FAKEVRTGGM AFHSYFME A IAPPLLQELK KVIREPKPRS ARWLSTSIPE AQWHSSLART SSAEYNVNNL VSPVLFQEAL WHVPEHAVVL EIAPHALLQ AVLKRGLKPS CTIIPLMKKD HRDNLEFFLA GIGRLHLSGI DANPNALFPP VEFPAPRGTP LISPLIKWDH SLAWDVPAAE DFPNGSGSP SAAIYNIDTS SESPDHYLVD HTLDGRVLFP ATGYLSIVWK TLARALGLGV EQLPVVFEDV VLHQATILPK T GTVSLEVR LLEASRAFEV SENGNLVVSG KVYQWDDPDP RLFDHPESPT PNPTEPLFLA QAEVYKELRL RGYDYGPHFQ GI LEASLEG DSGRLLWKDN WVSFMDTMLQ MSILGSAKHG LYLPTRVTAI HIDPATHRQK LYTLQDKAQV ADVVVSRWLR VTV AGGVHI SGLHTESAPR RQQEQQVPIL EKFCFTPHTE EGCLSERAAL QEELQLCKGL VQALQTTVTQ QGLKMVVPGL DGAQ IPRDP SQQELPRLLS AACRLQLNGN LQLELAQVLA QERPKLPEDP LLSGLLDSPA LKACLDTAVE NMPSLKMKVV EVLAG HGHL YSRIPGLLSP HPLLQLSYTA TDRHPQALEA AQAELQQHDV AQGQWDPADP APSALGSADL LVCNCAVAAL GDPASA LSN MVAALREGGF LLLHTLLRGH PLGDIVAFLT STEPQYGQGI LSQDAWESLF SRVSLRLVGL KKSFYGSTLF LCRRPTP QD SPIFLPVDDT SFRWVESLKG ILADEDSSRP VWLKAINCAT SGVVGLVNCL RREPGGNRLR CVLLSNLSST SHVPEVDP G SAELQKVLQG DLVMNVYRDG AWGAFRHFLL EEDKPEEPTA HAFVSTLTRG DLSSIRWVCS SLRHAQPTCP GAQLCTVYY ASLNFRDIML ATGKLSPDAI PGKWTSQDSL LGMEFSGRDA SGKRVMGLVP AKGLATSVLL SPDFLWDVPS NWTLEEAASV PVVYSTAYY ALVVRGRVRP GETLLIHSGS GGVGQAAIAI ALSLGCRVFT TVGSAEKRAY LQARFPQLDS TSFANSRDTS F EQHVLWHT GGKGVDLVLN SLAEEKLQAS VRCLATHGRF LEIGKFDLSQ NHPLGMAIFL KNVTFHGVLL DAFFNESSAD WR EVWALVQ AGIRDGVVRP LKCTVFHGAQ VEDAFRYMAQ GKHIGKVVVQ VLAEEPEAVL KGAKPKLMSA ISKTFCPAHK SYI IAGGLG GFGLELAQWL IQRGVQKLVL TSRSGIRTGY QAKQVRRWRR QGVQVQVSTS NISSLEGARG LIAEAAQLGP VGGV FNLAV VLRDGLLENQ TPEFFQDVCK PKYSGTLNLD RVTREACPEL DYFVVFSSVS CGRGNAGQSN YGFANSAMER ICEKR RHEG LPGLAVQWGA IGDVGILVET MSTNDTIVSG TLPQRMASCL EVLDLFLNQP HMVLSSFVLA EKAAAYRDRD SQRDLV EAV AHILGIRDLA AVNLDSSLAD LGLDSLMSVE VRQTLERELN LVLSVREVRQ LTLRKLQELS SKADEASELA CPTPKED GL AQQQTQLNLR SLLVNPEGPT LMRLNSVQSS ERPLFLVHPI EGSTTVFHSL ASRLSIPTYG LQCTRAAPLD SIHSLAAY Y IDCIRQVQPE GPYRVAGYSY GACVAFEMCS QLQAQQSPAP THNSLFLFDG SPTYVLAYTQ SYRAKLTPGC EAEAETEAI CFFVQQFTDM EHNRVLEALL PLKGLEERVA AAVDLIIKSH QGLDRQELSF AARSFYYKLR AAEQYTPKAK YHGNVMLLRA KTGGAYGED LGADYNLSQV CDGKVSVHVI EGDHRTLLEG SGLESIISII HSSLAEPRVS VREGLEHHHH HHHH

UniProtKB: Fatty acid synthase

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Macromolecule #2: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

MacromoleculeName: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
type: ligand / ID: 2 / Number of copies: 4 / Formula: NDP
Molecular weightTheoretical: 745.421 Da
Chemical component information

ChemComp-NDP:
NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

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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 / Material: COPPER / Mesh: 300 / 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

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4) / Number images used: 114182
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC

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Atomic model buiding 1

Initial modelPDB ID:

3hhd


Chain - Residue range: 2-852 / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8vm0:
Composite structure of human FASN with NADPH in State 4

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