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

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Basic information

Entry
Database: PDB / ID: 7mhd
TitleThioesterase Domain of Human Fatty Acid Synthase (FASN-TE) binding a competitive inhibitor SBP-7635
ComponentsFatty acid synthase
KeywordsHydrolase/Inhibitor / THIOESTERASE DOMAIN / FATTY ACID SYNTHASE / Hydrolase-Inhibitor complex
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) / establishment of endothelial intestinal barrier / [acyl-carrier-protein] S-acetyltransferase / [acyl-carrier-protein] S-acetyltransferase activity / glycogen granule ...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) / establishment of endothelial intestinal barrier / [acyl-carrier-protein] S-acetyltransferase / [acyl-carrier-protein] S-acetyltransferase activity / glycogen granule / Fatty acyl-CoA biosynthesis / host-mediated perturbation of viral process / enoyl-[acyl-carrier-protein] reductase (NADPH) activity / [acyl-carrier-protein] S-malonyltransferase / [acyl-carrier-protein] S-malonyltransferase activity / ChREBP activates metabolic gene expression / 3-hydroxyacyl-[acyl-carrier-protein] dehydratase / beta-ketoacyl-[acyl-carrier-protein] synthase I / (3R)-hydroxyacyl-[acyl-carrier-protein] dehydratase activity / acetyl-CoA metabolic process / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / 3-oxoacyl-[acyl-carrier-protein] reductase / 3-oxoacyl-[acyl-carrier-protein] reductase (NADPH) activity / oleoyl-[acyl-carrier-protein] hydrolase / fatty acyl-[ACP] hydrolase activity / mammary gland development / fatty acid synthase activity / monocyte differentiation / phosphopantetheine binding / 3-oxoacyl-[acyl-carrier-protein] synthase activity / response to nutrient / cellular response to interleukin-4 / Activation of gene expression by SREBF (SREBP) / fatty acid metabolic process / osteoblast differentiation / fatty acid biosynthetic process / melanosome / cadherin binding / inflammatory response / Golgi apparatus / RNA binding / extracellular exosome / identical protein binding / 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 and metazoan fatty acid synthase dehydratase (PKS/mFAS DH) domain profile. / Polyketide synthase, dehydratase domain superfamily / 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 / Zinc-binding dehydrogenase / Acyl transferase / Acyl transferase domain / Acyl transferase domain in polyketide synthase (PKS) enzymes. / Acyl transferase domain superfamily / Acyl transferase/acyl hydrolase/lysophospholipase / Polyketide synthase, enoylreductase domain / Enoylreductase / Polyketide synthase, phosphopantetheine-binding domain / Phosphopantetheine attachment site / Beta-ketoacyl synthase, active site / Ketosynthase family 3 (KS3) active site signature. / PKS_KR / 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
Chem-ZEP / Fatty acid synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.03 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 / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

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Assembly

Deposited unit
A: Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9292
Polymers32,5251
Non-polymers4051
Water1,910106
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)53.886, 61.486, 77.450
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-ZEP / N,N-diethyl-4-{2-[(2-fluorophenyl)methyl]-1,3-thiazol-4-yl}benzene-1-sulfonamide


Mass: 404.521 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21FN2O2S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / 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: 1.97 Å3/Da / Density % sol: 37.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 0.3 ul of 8 mg/ml FASN-TE in 100 mM NaCl, 50 mM BisTris pH 6.0, 10 mM DTT, 0.5 mM of the inhibitor and 1% DMSO were mixed with 0.2 ul of well solution 10% PEG400, 50 mM TRIS-Cl pH 8.5, 1 mM ...Details: 0.3 ul of 8 mg/ml FASN-TE in 100 mM NaCl, 50 mM BisTris pH 6.0, 10 mM DTT, 0.5 mM of the inhibitor and 1% DMSO were mixed with 0.2 ul of well solution 10% PEG400, 50 mM TRIS-Cl pH 8.5, 1 mM DTT, 1 mM Ethylenediaminetetraacetic acid disodium salt (EDTA), 300 mM NaCl.
PH range: pH 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: 1.0332 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 2→35.93 Å / Num. obs: 16885 / % possible obs: 98.2 % / Redundancy: 4.5 % / Biso Wilson estimate: 39.2 Å2 / Rmerge(I) obs: 0.049 / Net I/σ(I): 15.1
Reflection shellResolution: 2.03→2.08 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.618 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 1031 / % possible all: 82.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0257refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TJM

3tjm


Resolution: 2.03→35.93 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.936 / SU B: 6.13 / SU ML: 0.164 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.242 / ESU R Free: 0.197 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2457 824 4.9 %RANDOM
Rwork0.1928 ---
obs0.1956 16028 97.86 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 109.57 Å2 / Biso mean: 42.494 Å2 / Biso min: 23.58 Å2
Baniso -1Baniso -2Baniso -3
1-0.61 Å20 Å20 Å2
2---1.91 Å20 Å2
3---1.31 Å2
Refinement stepCycle: final / Resolution: 2.03→35.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2189 0 27 106 2322
Biso mean--59.91 46.3 -
Num. residues----282
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0132321
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172114
X-RAY DIFFRACTIONr_angle_refined_deg1.5261.6583158
X-RAY DIFFRACTIONr_angle_other_deg1.2891.5774909
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3085291
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.78221.901121
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.4315379
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1841516
X-RAY DIFFRACTIONr_chiral_restr0.0720.2298
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022632
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02492
LS refinement shellResolution: 2.03→2.083 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.305 37 -
Rwork0.283 991 -
all-1028 -
obs--81.33 %

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