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- EMDB-40182: Atomic model of the core modifying region of human fatty acid syn... -

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Basic information

Entry
Database: EMDB / ID: EMD-40182
TitleAtomic model of the core modifying region of human fatty acid synthase in complex with TVB-2640 - C2 refinement
Map dataSharpened map
Sample
  • Complex: Fatty acid synthase
    • Protein or peptide: Fatty acid synthase
  • Ligand: denifanstat
  • Ligand: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
KeywordsFatty acid synthase / TRANSFERASE / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


fatty-acid synthase system / (3R)-3-hydroxybutanoyl-[acyl-carrier-protein] hydratase activity / ether lipid biosynthetic process / : / : / (3R)-3-hydroxyoctanoyl-[acyl-carrier-protein] dehydratase activity / Vitamin B5 (pantothenate) metabolism / neutrophil differentiation / enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific) / (3R)-3-hydroxydecanoyl-[acyl-carrier-protein] dehydratase activity ...fatty-acid synthase system / (3R)-3-hydroxybutanoyl-[acyl-carrier-protein] hydratase activity / ether lipid biosynthetic process / : / : / (3R)-3-hydroxyoctanoyl-[acyl-carrier-protein] dehydratase activity / Vitamin B5 (pantothenate) metabolism / neutrophil differentiation / enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific) / (3R)-3-hydroxydecanoyl-[acyl-carrier-protein] dehydratase activity / glandular epithelial cell development / : / glycogen granule / establishment of endothelial intestinal barrier / [acyl-carrier-protein] S-acetyltransferase / [acyl-carrier-protein] S-acetyltransferase activity / Fatty acyl-CoA biosynthesis / oleoyl-[acyl-carrier-protein] hydrolase / (3R)-3-hydroxypalmitoyl-[acyl-carrier-protein] dehydratase activity / modulation by host of viral process / ChREBP activates metabolic gene expression / [acyl-carrier-protein] S-malonyltransferase / [acyl-carrier-protein] S-malonyltransferase activity / fatty acid synthase activity / 3-hydroxyacyl-[acyl-carrier-protein] dehydratase / (3R)-3-hydroxymyristoyl-[acyl-carrier-protein] dehydratase activity / beta-ketoacyl-[acyl-carrier-protein] synthase I / 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 / phosphopantetheine binding / monocyte differentiation / 3-oxoacyl-[acyl-carrier-protein] synthase activity / cellular response to interleukin-4 / fatty acid metabolic process / Activation of gene expression by SREBF (SREBP) / osteoblast differentiation / fatty acid biosynthetic process / 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 / Polyketide and metazoan fatty acid synthase dehydratase (PKS/mFAS DH) domain profile. / Methyltransferase type 12 / Methyltransferase domain / : / Polyketide synthase dehydratase domain / Thioesterase / Thioesterase domain / PKS_DH ...: / Fatty acid synthase, pseudo-KR domain / Polyketide and metazoan fatty acid synthase dehydratase (PKS/mFAS DH) domain profile. / Methyltransferase type 12 / Methyltransferase domain / : / Polyketide synthase dehydratase domain / Thioesterase / Thioesterase domain / PKS_DH / Polyketide synthase, dehydratase domain / Polyketide synthase, dehydratase domain superfamily / Polyketide synthase, ketoreductase domain / KR domain / Polyketide synthase, C-terminal extension / Ketoacyl-synthetase C-terminal extension / Malonyl-CoA ACP transacylase, ACP-binding / PKS_KR / Acyl transferase domain superfamily / Acyl transferase / Acyl transferase domain / Acyl transferase domain in polyketide synthase (PKS) enzymes. / Acyl transferase/acyl hydrolase/lysophospholipase / Alcohol dehydrogenase-like, C-terminal / Zinc-binding dehydrogenase / Polyketide synthase, enoylreductase domain / Enoylreductase / Ketosynthase family 3 (KS3) domain profile. / Polyketide synthase, phosphopantetheine-binding domain / Phosphopantetheine attachment site / Beta-ketoacyl synthase / Beta-ketoacyl synthase, active site / Ketosynthase family 3 (KS3) active site signature. / Polyketide synthase, beta-ketoacyl synthase domain / Beta-ketoacyl synthase, N-terminal / Beta-ketoacyl synthase, C-terminal / Beta-ketoacyl synthase, N-terminal domain / Beta-ketoacyl synthase, C-terminal domain / GroES-like superfamily / Phosphopantetheine attachment site / Thiolase-like / 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: 2.45 Å
AuthorsHasan SMN / Keszei A / Mazhab-Jafari MT
Funding support Canada, 2 items
OrganizationGrant numberCountry
Canadian Institutes of Health Research (CIHR)419240 Canada
Natural Sciences and Engineering Research Council (NSERC, Canada)RGPIN-2018-06070 Canada
CitationJournal: Nat Commun / Year: 2023
Title: Atomic model for core modifying region of human fatty acid synthase in complex with Denifanstat.
Authors: S M Naimul Hasan / Jennifer W Lou / Alexander F A Keszei / David L Dai / Mohammad T Mazhab-Jafari /
Abstract: Fatty acid synthase (FASN) catalyzes the de novo synthesis of palmitate, a 16-carbon chain fatty acid that is the primary precursor of lipid metabolism and an important intracellular signaling ...Fatty acid synthase (FASN) catalyzes the de novo synthesis of palmitate, a 16-carbon chain fatty acid that is the primary precursor of lipid metabolism and an important intracellular signaling molecule. FASN is an attractive drug target in diabetes, cancer, fatty liver diseases, and viral infections. Here, we develop an engineered full-length human FASN (hFASN) that enables isolation of the condensing and modifying regions of the protein post-translation. The engineered protein enables electron cryo-microscopy (cryoEM) structure determination of the core modifying region of hFASN to 2.7 Å resolution. Examination of the dehydratase dimer within this region reveals that unlike its close homolog, porcine FASN, the catalytic cavity is close-ended and is accessible only through one opening in the vicinity of the active site. The core modifying region exhibits two major global conformational variabilities that describe long-range bending and twisting motions of the complex in solution. Finally, we solved the structure of this region bound to an anti-cancer drug, Denifanstat (i.e., TVB-2640), demonstrating the utility of our approach as a platform for structure guided design of future hFASN small molecule inhibitors.
History
DepositionMar 17, 2023-
Header (metadata) releaseMay 24, 2023-
Map releaseMay 24, 2023-
UpdateJul 5, 2023-
Current statusJul 5, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40182.png

Downloads & links

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Map

FileDownload / File: emd_40182.map.gz / Format: CCP4 / Size: 59.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Voxel sizeX=Y=Z: 1.03 Å
Density
Contour LevelBy AUTHOR: 2.0
Minimum - Maximum-13.826658999999999 - 19.920458
Average (Standard dev.)-0.00053210347 (±0.5202896)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions250250250
Spacing250250250
CellA=B=C: 257.5 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map B

Fileemd_40182_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_40182_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 : Fatty acid synthase

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

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Supramolecule #1: Fatty acid synthase

SupramoleculeName: Fatty acid synthase / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 340 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: 182.749016 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GGSPSAAIYN IDTSSESPDH YLVDHTLDGR VLFPATGYLS IVWKTLARAL GLGVEQLPVV FEDVVLHQAT ILPKTGTVSL EVRLLEASR AFEVSENGNL VVSGKVYQWD DPDPRLFDHP ESPTPNPTEP LFLAQAEVYK ELRLRGYDYG PHFQGILEAS L EGDSGRLL ...String:
GGSPSAAIYN IDTSSESPDH YLVDHTLDGR VLFPATGYLS IVWKTLARAL GLGVEQLPVV FEDVVLHQAT ILPKTGTVSL EVRLLEASR AFEVSENGNL VVSGKVYQWD DPDPRLFDHP ESPTPNPTEP LFLAQAEVYK ELRLRGYDYG PHFQGILEAS L EGDSGRLL WKDNWVSFMD TMLQMSILGS AKHGLYLPTR VTAIHIDPAT HRQKLYTLQD KAQVADVVVS RWLRVTVAGG VH ISGLHTE SAPRRQQEQQ VPILEKFCFT PHTEEGCLSE RAALQEELQL CKGLVQALQT KVTQQGLKMV VPGLDGAQIP RDP SQQELP RLLSAACRLQ LNGNLQLELA QVLAQERPKL PEDPLLSGLL DSPALKACLD TAVENMPSLK MKVVEVLAGH GHLY SRIPG LLSPHPLLQL SYTATDRHPQ ALEAAQAELQ QHDVAQGQWD PADPAPSALG SADLLVCNCA VAALGDPASA LSNMV AALR EGGFLLLHTL LRGHPLGDIV AFLTSTEPQY GQGILSQDAW ESLFSRVSLR LVGLKKSFYG STLFLCRRPT PQDSPI FLP VDDTSFRWVE SLKGILADED SSRPVWLKAI NCATSGVVGL VNCLRREPGG NRLRCVLLSN LSSTSHVPEV DPGSAEL QK VLQGDLVMNV YRDGAWGAFR HFLLEEDKPE EPTAHAFVST LTRGDLSSIR WVCSSLRHAQ PTCPGAQLCT VYYASLNF R DIMLATGKLS PDAIPGKWTS QDSLLGMEFS GRDASGKRVM GLVPAKGLAT SVLLSPDFLW DVPSNWTLEE AASVPVVYS TAYYALVVRG RVRPGETLLI HSGSGGVGQA AIAIALSLGC RVFTTVGSAE KRAYLQARFP QLDSTSFANS RDTSFEQHVL WHTGGKGVD LVLNSLAEEK LQASVRCLAT HGRFLEIGKF DLSQNHPLGM AIFLKNVTFH GVLLDAFFNE SSADWREVWA L VQAGIRDG VVRPLKCTVF HGAQVEDAFR YMAQGKHIGK VVVQVLAEEP EAVLKGAKPK LMSAISKTFC PAHKSYIIAG GL GGFGLEL AQWLIQRGVQ KLVLTSRSGI RTGYQAKQVR RWRRQGVQVQ VSTSNISSLE GARGLIAEAA QLGPVGGVFN LAV VLRDGL LENQTPEFFQ DVCKPKYSGT LNLDRVTREA CPELDYFVVF SSVSCGRGNA GQSNYGFANS AMERICEKRR HEGL PGLAV QWGAIGDVGI LVETMSTNDT IVSGTLPQRM ASCLEVLDLF LNQPHMVLSS FVLAEKAAAY RDRDSQRDLV EAVAH ILGI RDLAAVNLDS SLADLGLDSL MSVEVRQTLE RELNLVLSVR EVRQLTLRKL QELSSKADEA SELACPTPKE DGLAQQ QTQ LNLRSLLVNP EGPTLMRLNS VQSSERPLFL VHPIEGSTTV FHSLASRLSI PTYGLQCTRA APLDSIHSLA AYYIDCI RQ VQPEGPYRVA GYSYGACVAF EMCSQLQAQQ SPAPTHNSLF LFDGSPTYVL AYTQSYRAKL TPGCEAEAET EAICFFVQ Q FTDMEHNRVL EALLPLKGLE ERVAAAVDLI IKSHQGLDRQ ELSFAARSFY YKLRAAEQYT PKAKYHGNVM LLRAKTGGA YGEDLGADYN LSQVCDGKVS VHVIEGDHRT LLEGSGLESI ISIIHSSLAE PRVSVREGLE SRGPHHHHHH

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Macromolecule #2: denifanstat

MacromoleculeName: denifanstat / type: ligand / ID: 2 / Number of copies: 2 / Formula: X5O
Molecular weightTheoretical: 439.552 Da
Chemical component information

ChemComp-X5O:
denifanstat

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Macromolecule #3: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE

MacromoleculeName: NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
type: ligand / ID: 3 / Number of copies: 4 / Formula: NDP
Molecular weightTheoretical: 745.421 Da
Chemical component information

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

Concentration0.8 mg/mL
BufferpH: 7.4
GridModel: Homemade / Material: COPPER/RHODIUM / Mesh: 400 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.6 µm
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 4801 / Average electron dose: 50.76 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3)
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.45 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.0.2) / Number images used: 311983

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8gkc:
Atomic model of the core modifying region of human fatty acid synthase in complex with TVB-2640 - C2 refinement

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