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- PDB-4piv: Human Fatty Acid Synthase Psi/KR Tri-Domain with NADPH and GSK2194069 -

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Basic information

Entry
Database: PDB / ID: 4piv
TitleHuman Fatty Acid Synthase Psi/KR Tri-Domain with NADPH and GSK2194069
ComponentsFatty acid synthase
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / fatty acid synthase / human FAS / keto-reductase / 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 / neutrophil differentiation / Vitamin B5 (pantothenate) metabolism / enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific) / glandular epithelial cell development ...fatty-acid synthase system / (3R)-3-hydroxybutanoyl-[acyl-carrier-protein] hydratase activity / ether lipid biosynthetic process / : / : / (3R)-3-hydroxyoctanoyl-[acyl-carrier-protein] dehydratase activity / neutrophil differentiation / Vitamin B5 (pantothenate) metabolism / enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific) / glandular epithelial cell development / (3R)-3-hydroxydecanoyl-[acyl-carrier-protein] dehydratase activity / : / 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. / Alcohol dehydrogenase-like, C-terminal / Acyl transferase/acyl hydrolase/lysophospholipase / 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 / Phosphopantetheine attachment site. / Thiolase-like / Phosphopantetheine attachment site / ACP-like superfamily / Carrier protein (CP) domain profile. / Phosphopantetheine binding ACP domain / Alpha/Beta hydrolase fold / NAD(P)-binding Rossmann-like Domain / NAD(P)-binding domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-2W4 / CACODYLATE ION / Chem-NDP / Fatty acid synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.299 Å
AuthorsWilliams, S.P. / Wang, L. / Brown, K.K. / Parrish, C.A. / Hardwicke, M.A.
CitationJournal: Nat.Chem.Biol. / Year: 2014
Title: A human fatty acid synthase inhibitor binds beta-ketoacyl reductase in the keto-substrate site.
Authors: Hardwicke, M.A. / Rendina, A.R. / Williams, S.P. / Moore, M.L. / Wang, L. / Krueger, J.A. / Plant, R.N. / Totoritis, R.D. / Zhang, G. / Briand, J. / Burkhart, W.A. / Brown, K.K. / Parrish, C.A.
History
DepositionMay 9, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 23, 2014Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2014Group: Database references
Revision 1.2Aug 20, 2014Group: Database references
Revision 1.3Oct 1, 2014Group: Database references
Revision 1.4Nov 22, 2017Group: Derived calculations / Other ...Derived calculations / Other / Refinement description / Source and taxonomy
Category: entity_src_gen / pdbx_database_status ...entity_src_gen / pdbx_database_status / pdbx_struct_assembly / pdbx_struct_conn_angle / pdbx_struct_oper_list / software
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible ..._entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_assembly.oligomeric_details / _pdbx_struct_oper_list.symmetry_operation
Revision 1.5Jul 17, 2019Group: Data collection / Refinement description / Category: software / Item: _software.name / _software.version
Revision 1.6Dec 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / refine_hist / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.number_atoms_total / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Fatty acid synthase
B: Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,70212
Polymers143,6962
Non-polymers3,00610
Water3,963220
1
A: Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,3516
Polymers71,8481
Non-polymers1,5035
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,3516
Polymers71,8481
Non-polymers1,5035
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.221, 85.761, 85.995
Angle α, β, γ (deg.)65.490, 89.960, 87.220
Int Tables number1
Space group name H-MP1
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: GLN / Beg label comp-ID: GLN / End auth comp-ID: GLU / End label comp-ID: GLU / Refine code: 0 / Auth seq-ID: 1110 - 2113 / Label seq-ID: 2 - 653

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Fatty acid synthase /


Mass: 71848.188 Da / Num. of mol.: 2
Fragment: Psi/KR Tri-Domain (UNP residues 1110-1524, 1877-2114)
Mutation: del(E1525-I1876), P1524G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FASN, FAS / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P49327, fatty-acid synthase system

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Non-polymers , 5 types, 230 molecules

#2: Chemical ChemComp-CAC / CACODYLATE ION / dimethylarsinate / Cacodylic acid


Mass: 136.989 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6AsO2
#3: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE / Nicotinamide adenine dinucleotide phosphate


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-2W4 / 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one


Mass: 428.483 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H24N4O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 220 / 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: 2.25 Å3/Da / Density % sol: 45.3 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.6
Details: 25% PEG3350, 0.19 M ammonium sulfate, 5 mM sodium cacodylate, pH 7.6
PH range: 6.5 - 7.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Mar 5, 2012
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionRedundancy: 3.9 % / Number: 233271 / Rsym value: 0.057 / D res high: 2.227 Å / D res low: 78.227 Å / Num. obs: 60106 / % possible obs: 98.1
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsRsym valueRedundancy
7.0478.2310.0250.0253.7
4.987.0410.030.033.8
4.074.9810.0290.0293.8
3.524.0710.0340.0343.8
3.153.5210.0510.0513.9
2.883.1510.0820.0823.9
2.662.8810.1320.1323.9
2.492.6610.210.213.9
2.352.4910.3070.3073.9
2.232.3510.4370.4373.9
ReflectionResolution: 2.227→78.227 Å / Num. all: 60106 / Num. obs: 60106 / % possible obs: 98.1 % / Redundancy: 3.9 % / Biso Wilson estimate: 37.165 Å2 / Rpim(I) all: 0.04 / Rrim(I) all: 0.079 / Rsym value: 0.057 / Net I/av σ(I): 11.514 / Net I/σ(I): 13 / Num. measured all: 233271
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2.227-2.353.90.4371.83434587410.310.4372.697.5
2.35-2.493.90.3072.53248082590.220.3073.697.8
2.49-2.663.90.213.73062678200.150.215.298
2.66-2.883.90.1325.92845972870.0940.132898.2
2.88-3.153.90.0829.32604366890.0590.0821298.5
3.15-3.523.90.05114.32349560900.0360.05117.998.6
3.52-4.073.80.034202045653440.0240.03425.498.4
4.07-4.983.80.02922.71711544860.020.02930.598.1
4.98-7.043.80.0321.21325135060.0220.0329.498.6
7.04-78.2273.70.02523.5700118840.0180.02535.397.3

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation29.53 Å2.55 Å

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Processing

Software
NameVersionClassification
REFMAC5.6.0109refinement
SCALAdata scaling
PDB_EXTRACT3.14data extraction
MOLREP11.0.02phasing
BUSTERrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.299→28.55 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.923 / WRfactor Rfree: 0.2379 / WRfactor Rwork: 0.2083 / FOM work R set: 0.8646 / SU B: 11.556 / SU ML: 0.137 / SU R Cruickshank DPI: 0.0958 / SU Rfree: 0.0539 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.096 / ESU R Free: 0.054 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.2457 3898 7.3 %RANDOM
Rwork0.2139 49197 --
obs0.2162 53095 95.4 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 78.67 Å2 / Biso mean: 23.875 Å2 / Biso min: 15.35 Å2
Baniso -1Baniso -2Baniso -3
1--9.22 Å29.76 Å2-0.84 Å2
2--4.8 Å2-5.31 Å2
3---4.42 Å2
Refinement stepCycle: final / Resolution: 2.299→28.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8937 0 188 220 9345
Biso mean--25.79 33.79 -
Num. residues----1220
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0199320
X-RAY DIFFRACTIONr_bond_other_d0.0020.026103
X-RAY DIFFRACTIONr_angle_refined_deg1.1171.98712713
X-RAY DIFFRACTIONr_angle_other_deg0.933314923
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.04251210
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.10623.593334
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.853151393
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.6581556
X-RAY DIFFRACTIONr_chiral_restr0.0910.21489
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02110391
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021843
Refine LS restraints NCS

Ens-ID: 1 / Number: 20461 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.08 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.299→2.358 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.311 271 -
Rwork0.273 3554 -
all-3825 -
obs--94.58 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)DetailsOrigin x (Å)Origin y (Å)Origin z (Å)
10.6785-0.28260.55160.714-0.60131.111-0.0253-0.08330.0731-0.021-0.02740.00410.02570.00930.05270.00450.00880.00110.0203-0.00810.1135C4.77-1.752-22.616
20.6163-0.4894-0.09311.50120.09550.4046-0.00890.00550.0311-0.0184-0.00990.053-0.03140.05710.01880.0261-0.0265-0.04460.03740.02820.1041-4.8881.99623.118
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1109 - 2113
2X-RAY DIFFRACTION1A2201
3X-RAY DIFFRACTION1A2202
4X-RAY DIFFRACTION1A2205
5X-RAY DIFFRACTION2B1110 - 2113
6X-RAY DIFFRACTION2B2201
7X-RAY DIFFRACTION2B2202
8X-RAY DIFFRACTION2B2205

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