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- PDB-3hhd: Structure of the Human Fatty Acid Synthase KS-MAT Didomain as a F... -

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Basic information

Entry
Database: PDB / ID: 3hhd
TitleStructure of the Human Fatty Acid Synthase KS-MAT Didomain as a Framework for Inhibitor Design.
ComponentsFatty acid synthase
KeywordsTransferase / Hydrolase / FATTY ACID SYNTHASE / MULTIENZYME / MEGASYNTHASE / FATTY ACID SYNTHESIS / Acetylation / Cytoplasm / Fatty acid biosynthesis / Lipid synthesis / Lyase / Multifunctional enzyme / NAD / NADP / Oxidoreductase / Phosphopantetheine / Phosphoprotein / Pyridoxal phosphate
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
Helix Hairpins - #1960 / Alpha-Beta Plaits - #3290 / : / Fatty acid synthase, pseudo-KR domain / Malonyl-CoA ACP transacylase, ACP-binding / Malonyl-Coenzyme A Acyl Carrier Protein, domain 2 / Malonyl-Coenzyme A Acyl Carrier Protein; domain 2 / Polyketide and metazoan fatty acid synthase dehydratase (PKS/mFAS DH) domain profile. / Methyltransferase type 12 / Methyltransferase domain ...Helix Hairpins - #1960 / Alpha-Beta Plaits - #3290 / : / Fatty acid synthase, pseudo-KR domain / Malonyl-CoA ACP transacylase, ACP-binding / Malonyl-Coenzyme A Acyl Carrier Protein, domain 2 / Malonyl-Coenzyme A Acyl Carrier Protein; domain 2 / 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 / Thiolase/Chalcone synthase / Polyketide synthase, enoylreductase domain / Enoylreductase / Peroxisomal Thiolase; Chain A, domain 1 / 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 / Helix Hairpins / Alpha/Beta hydrolase fold / Alpha-Beta Plaits / NAD(P)-binding domain superfamily / S-adenosyl-L-methionine-dependent methyltransferase superfamily / 2-Layer Sandwich / Orthogonal Bundle / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsPappenberger, G.M. / Benz, J. / Thoma, R. / Rudolph, M.G.
CitationJournal: J.Mol.Biol. / Year: 2010
Title: Structure of the human fatty acid synthase KS-MAT didomain as a framework for inhibitor design.
Authors: Pappenberger, G. / Benz, J. / Gsell, B. / Hennig, M. / Ruf, A. / Stihle, M. / Thoma, R. / Rudolph, M.G.
History
DepositionMay 15, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 9, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_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
C: Fatty acid synthase
D: Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)417,9806
Polymers417,9094
Non-polymers712
Water32,5711808
1
A: Fatty acid synthase
D: Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)208,9903
Polymers208,9542
Non-polymers351
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5510 Å2
ΔGint-40 kcal/mol
Surface area58750 Å2
MethodPISA
2
B: Fatty acid synthase
C: Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)208,9903
Polymers208,9542
Non-polymers351
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5530 Å2
ΔGint-39 kcal/mol
Surface area58870 Å2
MethodPISA
Unit cell
Length a, b, c (Å)86.620, 91.160, 132.110
Angle α, β, γ (deg.)73.84, 86.83, 62.54
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
Fatty acid synthase / / [Acyl-carrier-protein] S-acetyltransferase / [Acyl-carrier-protein] S-malonyltransferase / 3- ...[Acyl-carrier-protein] S-acetyltransferase / [Acyl-carrier-protein] S-malonyltransferase / 3-oxoacyl-[acyl-carrier-protein] synthase


Mass: 104477.172 Da / Num. of mol.: 4 / Fragment: UNP residues 2-963
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
#2: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1808 / 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: 2.12 Å3/Da / Density % sol: 41.97 %
Crystal growTemperature: 294 K / Method: microbatch under oil / pH: 6.5
Details: 0.1M MES pH 6.5, 0.1M NaCl, 12% PEG4000, microbatch under oil, temperature 294K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9796 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Oct 5, 2005
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9796 Å / Relative weight: 1
ReflectionResolution: 2.15→45.64 Å / Num. obs: 182578 / % possible obs: 97.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 2.6 % / Biso Wilson estimate: 27.287 Å2 / Rsym value: 0.093 / Net I/σ(I): 24.3
Reflection shellResolution: 2.15→2.23 Å / Redundancy: 2.2 % / Mean I/σ(I) obs: 2.5 / Num. unique all: 17566 / Rsym value: 0.361 / % possible all: 94.2

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Processing

Software
NameVersionClassification
MOLREPphasing
PHASERphasing
BUSTER-TNT2.5.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2vz9

2vz9


Resolution: 2.15→45.64 Å / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber / Details: used NCS
RfactorNum. reflection% reflectionSelection details
Rfree0.2108 9152 5.01 %RANDOM
Rwork0.1686 ---
obs0.1707 182506 97.35 %-
Displacement parametersBiso mean: 31.5 Å2
Baniso -1Baniso -2Baniso -3
1--8.45622659 Å21.76147164 Å26.78035413 Å2
2--3.40841656 Å2-4.11359802 Å2
3---5.04781003 Å2
Refine analyzeLuzzati coordinate error obs: 0.2192 Å
Refinement stepCycle: LAST / Resolution: 2.15→45.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms26026 0 2 1808 27836
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.007266732
X-RAY DIFFRACTIONt_angle_deg1.001360302
X-RAY DIFFRACTIONt_dihedral_angle_d19.31851830
X-RAY DIFFRACTIONt_trig_c_planes0.0075952
X-RAY DIFFRACTIONt_gen_planes0.01439505
X-RAY DIFFRACTIONt_it1.4482667320
X-RAY DIFFRACTIONt_nbd0.0372395
LS refinement shellResolution: 2.15→2.28 Å / Total num. of bins used: 9
RfactorNum. reflection% reflection
Rfree0.2325 1342 4.8 %
Rwork0.1987 26632 -
all0.2004 27974 -
obs--97.35 %

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