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- PDB-2px6: Crystal structure of the thioesterase domain of human fatty acid ... -

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Basic information

Entry
Database: PDB / ID: 2px6
TitleCrystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat
ComponentsThioesterase domain
KeywordsTRANSFERASE / thioesaterse domain / Orlistat / fatty acid synthase / drug complex / tetrahydrolipstatin
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; domain 2 / Protein Yjbj; Chain: A; / : / Fatty acid synthase, pseudo-KR domain / Methyltransferase type 12 / Methyltransferase domain / Thioesterase / Thioesterase domain / Polyketide synthase, dehydratase domain / PKS_DH ...Fatty acid synthase; domain 2 / Protein Yjbj; Chain: A; / : / 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, 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
Chem-DH9 / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / Fatty acid synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsPemble IV, C.W. / Johnson, L.C. / Kridel, S.J. / Lowther, W.T.
CitationJournal: Nat.Struct.Mol.Biol. / Year: 2007
Title: Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat.
Authors: Pemble, C.W. / Johnson, L.C. / Kridel, S.J. / Lowther, W.T.
History
DepositionMay 14, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 30, 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_conn / 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_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature
Remark 600HETEROGEN DH9 3000 forms an adduct with SER 2308 and is missing the O2* atom

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Thioesterase domain
B: Thioesterase domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,6445
Polymers69,4622
Non-polymers1,1823
Water95553
1
A: Thioesterase domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2452
Polymers34,7311
Non-polymers5141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Thioesterase domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,3993
Polymers34,7311
Non-polymers6682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)41.860, 94.320, 69.720
Angle α, β, γ (deg.)90.00, 95.82, 90.00
Int Tables number4
Space group name H-MP1211
Detailseach chain represents the biological unit

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Components

#1: Protein Thioesterase domain


Mass: 34731.203 Da / Num. of mol.: 2 / Fragment: Residues 2200-2511
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FAS / Plasmid: pET15b / Production host: Escherichia coli (E. coli) / Strain (production host): C41(DE3) / References: UniProt: P49327, fatty-acid synthase system
#2: Chemical ChemComp-DH9 / (2S,3S,5S)-5-[(N-FORMYL-L-LEUCYL)OXY]-2-HEXYL-3-HYDROXYHEXADECANOIC ACID


Mass: 513.750 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H55NO6
#3: Chemical ChemComp-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL


Mass: 154.251 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2S2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 53 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 37.53 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 4.3
Details: 50mM sodium dihydrogen phosphate, 30-35% PEG 3350, 30mM dithiothreitol, pH 4.3, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X12C / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→39.01 Å / Num. all: 21850 / Num. obs: 21850 / % possible obs: 96 % / Redundancy: 7.1 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 17
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 6.2 % / Rmerge(I) obs: 0.23 / Mean I/σ(I) obs: 6.2 / % possible all: 76.2

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
CBASSdata collection
d*TREKdata reduction
d*TREKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1XKT

1xkt


Resolution: 2.3→39.01 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.9 / SU B: 7.796 / SU ML: 0.196 / Cross valid method: THROUGHOUT / ESU R: 0.474 / ESU R Free: 0.282 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27276 1184 5.1 %RANDOM
Rwork0.225 ---
obs0.22753 21850 96.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 36.96 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å2-0.01 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 2.3→39.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4011 0 79 53 4143
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0224176
X-RAY DIFFRACTIONr_angle_refined_deg1.2731.9845641
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5575507
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.00823.622185
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.32215673
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.8841527
X-RAY DIFFRACTIONr_chiral_restr0.0840.2640
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023123
X-RAY DIFFRACTIONr_nbd_refined0.2050.21914
X-RAY DIFFRACTIONr_nbtor_refined0.3030.22844
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1660.2169
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2020.263
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.120.25
X-RAY DIFFRACTIONr_mcbond_it0.6611.52646
X-RAY DIFFRACTIONr_mcangle_it1.09324123
X-RAY DIFFRACTIONr_scbond_it1.47531707
X-RAY DIFFRACTIONr_scangle_it2.374.51518
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.374 70 -
Rwork0.231 1207 -
obs--73.01 %

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