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- PDB-7mhe: Thioesterase Domain of Human Fatty Acid Synthase (FASN-TE) bindin... -

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Basic information

Entry
Database: PDB / ID: 7mhe
TitleThioesterase Domain of Human Fatty Acid Synthase (FASN-TE) binding a competitive inhibitor SBP-7957
ComponentsFatty acid synthase
KeywordsHYDROLASE/Inhibitor / THIOESTERASE DOMAIN / FATTY ACID SYNTHASE / FASN-TE / HYDROLASE-Inhibitor complex
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 / mammary gland development / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / 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 / inflammatory response / cadherin binding / 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. / Acyl transferase domain superfamily / Alcohol dehydrogenase-like, C-terminal / 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. / 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 / 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-ZEG / Fatty acid synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsAleshin, A.E. / Lambert, L. / Liddington, R.C. / Cosford, N.
CitationJournal: To Be Published
Title: Thioesterase Domain of Human Fatty Acid Synthase (FASN-TE) binding a competitive inhibitor SBP-7635
Authors: Aleshin, A.E. / Lambert, L. / Liddington, R.C. / Cosford, N.
History
DepositionApr 15, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 20, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
AAA: Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9913
Polymers32,5251
Non-polymers4672
Water27015
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.680, 56.500, 75.640
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 32524.670 Da / Num. of mol.: 1 / Fragment: Thioesterase
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FASN, FAS / Production host: Escherichia coli (E. coli)
References: UniProt: P49327, oleoyl-[acyl-carrier-protein] hydrolase
#2: Chemical ChemComp-ZEG / 4-{4-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]benzene-1-sulfonyl}morpholine


Mass: 404.478 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H17FN2O3S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 15 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.73 Å3/Da / Density % sol: 28.92 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.3 uL of 8 mg/ml FAS-TE in 100 mM NaCl, 50 mM BisTris pH 6.0, 10 mM DTT, 0.5 mM of the inhibitor and 1% DMSO was mixed with 0.2 uL of well solution 10% PEG400, 50 mM Tris-Cl pH 8.5, 1.0 mM ...Details: 0.3 uL of 8 mg/ml FAS-TE in 100 mM NaCl, 50 mM BisTris pH 6.0, 10 mM DTT, 0.5 mM of the inhibitor and 1% DMSO was mixed with 0.2 uL of well solution 10% PEG400, 50 mM Tris-Cl pH 8.5, 1.0 mM DTT, 1.0 mM Ethylenediaminetetraacetic acid disodium salt (EDTA), 300 mM NaCl.
PH range: 6.0-8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 1.03316 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 9, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03316 Å / Relative weight: 1
ReflectionResolution: 2.8→45.3 Å / Num. obs: 5295 / % possible obs: 90.7 % / Redundancy: 4.6 % / Rmerge(I) obs: 0.2 / Net I/σ(I): 5.2
Reflection shellResolution: 2.8→2.9 Å / Rmerge(I) obs: 1.19 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 759

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TJM

3tjm


Resolution: 2.8→37.849 Å / Cor.coef. Fo:Fc: 0.939 / Cor.coef. Fo:Fc free: 0.876 / SU B: 25.392 / SU ML: 0.469 / Cross valid method: THROUGHOUT / ESU R Free: 0.558
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2836 291 5.496 %
Rwork0.2132 5004 -
all0.217 --
obs-5295 89.473 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 59.85 Å2
Baniso -1Baniso -2Baniso -3
1-2.675 Å20 Å20 Å2
2--2.409 Å20 Å2
3----5.085 Å2
Refinement stepCycle: LAST / Resolution: 2.8→37.849 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2165 0 31 15 2211
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0132244
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172051
X-RAY DIFFRACTIONr_ext_dist_refined_d0.0720.013474
X-RAY DIFFRACTIONr_angle_refined_deg1.4941.663045
X-RAY DIFFRACTIONr_angle_other_deg1.3031.5754758
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.455276
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.60721.826115
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.16415365
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8321515
X-RAY DIFFRACTIONr_chiral_restr0.0740.2288
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022505
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02472
X-RAY DIFFRACTIONr_nbd_refined0.2170.2524
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1820.22060
X-RAY DIFFRACTIONr_nbtor_refined0.1680.21101
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0820.21082
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1760.265
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2150.238
X-RAY DIFFRACTIONr_nbd_other0.2240.2122
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2360.23
X-RAY DIFFRACTIONr_mcbond_it3.3346.3361110
X-RAY DIFFRACTIONr_mcbond_other3.3336.3351109
X-RAY DIFFRACTIONr_mcangle_it5.3429.4971384
X-RAY DIFFRACTIONr_mcangle_other5.349.4991385
X-RAY DIFFRACTIONr_scbond_it3.1236.6661134
X-RAY DIFFRACTIONr_scbond_other3.1226.6651135
X-RAY DIFFRACTIONr_scangle_it5.2469.8731661
X-RAY DIFFRACTIONr_scangle_other5.2459.8721662
X-RAY DIFFRACTIONr_lrange_it11.22120.6439641
X-RAY DIFFRACTIONr_lrange_other11.22120.6459641
LS refinement shellResolution: 2.8→2.872 Å
RfactorNum. reflection% reflection
Rfree0.42 23 -
Rwork0.303 373 -
obs--94.2857 %

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