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- PDB-1xkt: Human fatty acid synthase: Structure and substrate selectivity of... -

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Basic information

Entry
Database: PDB / ID: 1xkt
TitleHuman fatty acid synthase: Structure and substrate selectivity of the thioesterase domain
Componentsfatty acid synthase
Keywordshydroxylase / Human fatty acid synthase / thioesterase / specificity / drug target
Function / homology
Function and homology information


fatty-acid synthase system / (3R)-3-hydroxybutanoyl-[acyl-carrier-protein] hydratase activity / fatty acyl-[ACP] hydrolase 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 ...fatty-acid synthase system / (3R)-3-hydroxybutanoyl-[acyl-carrier-protein] hydratase activity / fatty acyl-[ACP] hydrolase 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 / (3R)-3-hydroxymyristoyl-[acyl-carrier-protein] dehydratase 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 / phosphopantetheine binding / monocyte differentiation / 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; domain 2 / Protein Yjbj; Chain: A; / : / 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 ...Fatty acid synthase; domain 2 / Protein Yjbj; Chain: A; / : / 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 / Malonyl-CoA ACP transacylase, ACP-binding / Polyketide synthase, C-terminal extension / Ketoacyl-synthetase C-terminal extension / 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, catalytic domain / Alpha/Beta hydrolase fold / NAD(P)-binding domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Rossmann fold / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MAD / Resolution: 2.6 Å
AuthorsChakravarty, B. / Gu, Z. / Chirala, S.S. / Wakil, S.J. / Quiocho, F.A.
CitationJournal: Proc.Natl.Acad.Sci.Usa / Year: 2004
Title: Human fatty acid synthase: structure and substrate selectivity of the thioesterase domain.
Authors: Chakravarty, B. / Gu, Z. / Chirala, S.S. / Wakil, S.J. / Quiocho, F.A.
History
DepositionSep 29, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 26, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 14, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Remark 999SEQUENCE There is a mismatch in postion 2440 from the database reference sequence of fatty acid ...SEQUENCE There is a mismatch in postion 2440 from the database reference sequence of fatty acid synthase, which is due to the heteregeneity of that position in different clones.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: fatty acid synthase
B: fatty acid synthase


Theoretical massNumber of molelcules
Total (without water)63,5642
Polymers63,5642
Non-polymers00
Water1,17165
1
A: fatty acid synthase


Theoretical massNumber of molelcules
Total (without water)31,7821
Polymers31,7821
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: fatty acid synthase


Theoretical massNumber of molelcules
Total (without water)31,7821
Polymers31,7821
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)104.783, 104.783, 126.460
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number91
Space group name H-MP4122
DetailsMonomer is active biologically although assymetric unit has a dimer

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Components

#1: Protein fatty acid synthase /


Mass: 31782.041 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Plasmid: ProEx / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P49327
#2: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 65 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.938 Å3/Da / Density % sol: 58 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: Ammonium sulfate, MES, glycerol, pH 6.8, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 150 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X4A / Wavelength: 0.96865, 0.97930, 0.97910, 0.96390
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: Feb 8, 2002
RadiationMonochromator: KOHZU double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
10.968651
20.97931
30.97911
40.96391
ReflectionResolution: 2.6→50 Å / Num. all: 22088 / Num. obs: 21444 / % possible obs: 97.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Biso Wilson estimate: 46.4 Å2
Reflection shellResolution: 2.6→2.76 Å / % possible all: 92.5

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Processing

Software
NameVersionClassification
CNS1.1refinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MAD / Resolution: 2.6→11.82 Å / Rfactor Rfree error: 0.009 / Data cutoff high absF: 470097.2 / Data cutoff low absF: 0 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
Details: The active site, Ser 2308, has bad phi and psi values, as seen in serine-like proteases.
RfactorNum. reflection% reflectionSelection details
Rfree0.279 1043 4.9 %RANDOM
Rwork0.258 ---
all0.258 22088 --
obs0.258 21444 97.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 47.0189 Å2 / ksol: 0.338461 e/Å3
Displacement parametersBiso mean: 61.8 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å20 Å2
2---0.02 Å20 Å2
3---0.03 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.48 Å0.41 Å
Luzzati d res low-5 Å
Luzzati sigma a0.51 Å0.41 Å
Refinement stepCycle: LAST / Resolution: 2.6→11.82 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4046 0 0 65 4111
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d22.5
X-RAY DIFFRACTIONc_improper_angle_d0.86
LS refinement shellResolution: 2.6→2.76 Å / Rfactor Rfree error: 0.03 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.406 185 5.5 %
Rwork0.353 3174 -
obs--92.5 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAM

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