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- PDB-8eyi: Atomic model of the core modifying region of human fatty acid synthase -

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Basic information

Entry
Database: PDB / ID: 8eyi
TitleAtomic model of the core modifying region of human fatty acid synthase
ComponentsFatty acid synthase
KeywordsTRANSFERASE / Fatty acid synthase
Function / homology
Function and homology information


fatty-acid synthase system / : / : / : / ether lipid biosynthetic process / Vitamin B5 (pantothenate) metabolism / : / neutrophil differentiation / enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific) / glandular epithelial cell development ...fatty-acid synthase system / : / : / : / ether lipid biosynthetic process / Vitamin B5 (pantothenate) metabolism / : / neutrophil differentiation / enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific) / glandular epithelial cell development / glycogen granule / establishment of endothelial intestinal barrier / [acyl-carrier-protein] S-acetyltransferase / [acyl-carrier-protein] S-acetyltransferase activity / : / oleoyl-[acyl-carrier-protein] hydrolase / Fatty acyl-CoA biosynthesis / fatty acyl-[ACP] hydrolase activity / modulation by host of viral process / enoyl-[acyl-carrier-protein] reductase (NADPH) activity / ChREBP activates metabolic gene expression / [acyl-carrier-protein] S-malonyltransferase / [acyl-carrier-protein] S-malonyltransferase activity / 3-hydroxyacyl-[acyl-carrier-protein] dehydratase / 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 / 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 / : / Acyl transferase / Acyl transferase domain / Acyl transferase domain in polyketide synthase (PKS) enzymes. / Alcohol dehydrogenase-like, C-terminal / Acyl transferase domain superfamily / Zinc-binding dehydrogenase / Acyl transferase/acyl hydrolase/lysophospholipase / Polyketide synthase, enoylreductase domain / Enoylreductase / Polyketide synthase, phosphopantetheine-binding domain / Phosphopantetheine attachment site / Beta-ketoacyl synthase / Beta-ketoacyl synthase, active site / Ketosynthase family 3 (KS3) active site signature. / PKS_KR / 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
Chem-NDP / Fatty acid synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsHasan, S.M.N. / Keszei, A. / Mazhab-Jafari, M.T.
Funding support Canada, 2items
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
DepositionOct 27, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 24, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 5, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
E: Fatty acid synthase
F: Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)368,4806
Polymers365,4982
Non-polymers2,9824
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Fatty acid synthase / Type I fatty acid synthase


Mass: 182749.016 Da / Num. of mol.: 2 / Fragment: residues 855-2511
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FASN, FAS / Production host: Homo sapiens (human)
References: UniProt: P49327, fatty-acid synthase system, [acyl-carrier-protein] S-acetyltransferase, [acyl-carrier-protein] S-malonyltransferase, beta-ketoacyl-[acyl-carrier-protein] synthase I, 3- ...References: UniProt: P49327, fatty-acid synthase system, [acyl-carrier-protein] S-acetyltransferase, [acyl-carrier-protein] S-malonyltransferase, beta-ketoacyl-[acyl-carrier-protein] synthase I, 3-oxoacyl-[acyl-carrier-protein] reductase, 3-hydroxyacyl-[acyl-carrier-protein] dehydratase, enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific), oleoyl-[acyl-carrier-protein] hydrolase
#2: Chemical
ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H30N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Fatty acid synthase / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.34 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293 / Plasmid: pcDNA3.1
Buffer solutionpH: 7.4
SpecimenConc.: 0.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER/RHODIUM / Grid mesh size: 400 divisions/in. / Grid type: Homemade
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm
Image recordingElectron dose: 50.76 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4016

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameVersionCategoryDetails
1cryoSPARC3.3particle selection
2EPUimage acquisition
4cryoSPARC3.3CTF correctionPatch CFT
7PHENIX1.20.1-4487model fitting
8Coot0.9.6 ELmodel fitting
10cryoSPARC3.3initial Euler assignment
11cryoSPARC3.3final Euler assignment
13cryoSPARC3.33D reconstruction
14PHENIX1.20.1-4487model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 355649 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00316630
ELECTRON MICROSCOPYf_angle_d0.54822716
ELECTRON MICROSCOPYf_dihedral_angle_d8.0412414
ELECTRON MICROSCOPYf_chiral_restr0.0412618
ELECTRON MICROSCOPYf_plane_restr0.0042916

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