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- PDB-5c37: Structure of the beta-ketoacyl reductase domain of human fatty ac... -

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Basic information

Entry
Database: PDB / ID: 5c37
TitleStructure of the beta-ketoacyl reductase domain of human fatty acid synthase bound to a spiro-imidazolone inhibitor
ComponentsFatty acid synthase
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE Inhibitor / fatty acid synthase / inhibitor / beta-ketoacyl reductase / cancer / OXIDOREDUCTASE-OXIDOREDUCTASE 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) / glandular epithelial cell development / establishment of endothelial intestinal barrier / [acyl-carrier-protein] S-acetyltransferase / [acyl-carrier-protein] S-acetyltransferase activity ...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) / glandular epithelial cell development / establishment of endothelial intestinal barrier / [acyl-carrier-protein] S-acetyltransferase / [acyl-carrier-protein] S-acetyltransferase activity / glycogen granule / Fatty acyl-CoA biosynthesis / oleoyl-[acyl-carrier-protein] hydrolase / fatty acyl-[ACP] hydrolase activity / modulation by host of viral process / ChREBP activates metabolic gene expression / [acyl-carrier-protein] S-malonyltransferase / 3-hydroxyacyl-[acyl-carrier-protein] dehydratase / enoyl-[acyl-carrier-protein] reductase (NADPH) activity / [acyl-carrier-protein] S-malonyltransferase activity / beta-ketoacyl-[acyl-carrier-protein] synthase I / (3R)-hydroxyacyl-[acyl-carrier-protein] dehydratase activity / 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 / fatty acid synthase activity / monocyte differentiation / phosphopantetheine binding / 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 / cadherin binding / inflammatory response / 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 / : / Alcohol dehydrogenase-like, C-terminal / Acyl transferase / Acyl transferase domain / Acyl transferase domain in polyketide synthase (PKS) enzymes. / Zinc-binding dehydrogenase / Acyl transferase domain superfamily / Acyl transferase/acyl hydrolase/lysophospholipase / Polyketide synthase, enoylreductase domain / Enoylreductase / Polyketide synthase, phosphopantetheine-binding domain / Phosphopantetheine attachment site / PKS_KR / Beta-ketoacyl synthase, active site / Ketosynthase family 3 (KS3) active site signature. / 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 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-4XN / Chem-NDP / Fatty acid synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsSchubert, C. / Milligan, C.M. / Vo, K. / Grasberger, B.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2018
Title: Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy.
Authors: Lu, T. / Schubert, C. / Cummings, M.D. / Bignan, G. / Connolly, P.J. / Smans, K. / Ludovici, D. / Parker, M.H. / Meyer, C. / Rocaboy, C. / Alexander, R. / Grasberger, B. / De Breucker, S. / ...Authors: Lu, T. / Schubert, C. / Cummings, M.D. / Bignan, G. / Connolly, P.J. / Smans, K. / Ludovici, D. / Parker, M.H. / Meyer, C. / Rocaboy, C. / Alexander, R. / Grasberger, B. / De Breucker, S. / Esser, N. / Fraiponts, E. / Gilissen, R. / Janssens, B. / Peeters, D. / Van Nuffel, L. / Vermeulen, P. / Bischoff, J. / Meerpoel, L.
History
DepositionJun 17, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 22, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 27, 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 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Jun 19, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)146,72310
Polymers144,0982
Non-polymers2,6248
Water4,234235
1
A: Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,2984
Polymers72,0491
Non-polymers1,2483
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
C: Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,4256
Polymers72,0491
Non-polymers1,3765
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)94.080, 80.520, 96.530
Angle α, β, γ (deg.)90.00, 116.90, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AC

#1: Protein Fatty acid synthase


Mass: 72049.234 Da / Num. of mol.: 2
Fragment: PsiME/PsiKR/KR Tri-Domain (UNP residues 1108-1523, 1877-2122)
Mutation: F1880G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FASN, FAS / Plasmid: Bacmagic 2 / Cell (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P49327, fatty-acid synthase system, [acyl-carrier-protein] S-acetyltransferase, [acyl-carrier-protein] S-malonyltransferase, beta-ketoacyl-[acyl-carrier-protein] synthase I, 3- ...References: UniProt: P49327, fatty-acid synthase system, [acyl-carrier-protein] S-acetyltransferase, [acyl-carrier-protein] S-malonyltransferase, beta-ketoacyl-[acyl-carrier-protein] synthase I, 3-oxoacyl-[acyl-carrier-protein] reductase, 3-hydroxyacyl-[acyl-carrier-protein] dehydratase, enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific), oleoyl-[acyl-carrier-protein] hydrolase

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Non-polymers , 5 types, 243 molecules

#2: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3
#3: Chemical ChemComp-4XN / 6-{[(3R)-1-(cyclopropylcarbonyl)pyrrolidin-3-yl]methyl}-5-[4-(1-methyl-1H-indazol-5-yl)phenyl]-4,6-diazaspiro[2.4]hept-4-en-7-one


Mass: 467.562 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H29N5O2
#4: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 2.26 Å3/Da / Density % sol: 45.64 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: PEG3350, Tris, KCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 16, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.3→47 Å / Num. obs: 56916 / % possible obs: 99.1 % / Observed criterion σ(I): -3 / Redundancy: 3.4 % / Biso Wilson estimate: 45.25 Å2 / Rmerge F obs: 0.132 / Rmerge(I) obs: 0.057 / Rrim(I) all: 0.068 / Χ2: 1.054 / Net I/σ(I): 13.89 / Num. measured all: 191546
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge F obsRmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsRrim(I) all% possible all
2.3-2.363.21.0350.621.9912829418640610.74497
2.36-2.420.7740.5092.5513751414541330.60799.7
2.42-2.490.6190.4173.2713852396439480.49199.6
2.49-2.570.5130.373.9513598389338780.43799.6
2.57-2.660.3830.2775.0712970375437420.32899.7
2.66-2.750.3110.2156.2412435367636520.25599.3
2.75-2.850.2490.1817.2611547352535110.21799.6
2.85-2.970.180.1379.2411352339733860.16399.7
2.97-3.10.1220.10412.1211334326532460.12399.4
3.1-3.250.0930.07914.8810693309330730.09399.4
3.25-3.430.0730.06617.2310186297629590.07899.4
3.43-3.640.0540.04920.489038281527880.05999
3.64-3.890.0430.04224.088521264626160.0598.9
3.89-4.20.0330.03528.028203246724330.04298.6
4.2-4.60.0260.03232.497660226822420.03898.9
4.6-5.140.0270.03131.736642205620330.03798.9
5.14-5.940.030.03230.055704183118090.03998.8
5.94-7.270.0240.02835.265258155915450.03499.1
7.27-10.290.020.02439.273795120511840.02998.3
10.29-470.0170.02441.6721786976770.02897.1

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XSCALEJanuary 30, 2009data scaling
PDB_EXTRACT3.15data extraction
XDSJanuary 30, 2009data reduction
PHENIX1.9_1692phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2VZ9

2vz9


Resolution: 2.3→47 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 28.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2507 2029 3.57 %Random
Rwork0.2097 ---
obs0.2112 56850 99.24 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.3→47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9292 0 175 235 9702
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0039659
X-RAY DIFFRACTIONf_angle_d0.7413172
X-RAY DIFFRACTIONf_dihedral_angle_d12.9163465
X-RAY DIFFRACTIONf_chiral_restr0.0271525
X-RAY DIFFRACTIONf_plane_restr0.0041700
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.35750.35061410.30923774X-RAY DIFFRACTION97
2.3575-2.42130.31741270.29743923X-RAY DIFFRACTION100
2.4213-2.49250.30371370.28273876X-RAY DIFFRACTION99
2.4925-2.5730.33351520.27613911X-RAY DIFFRACTION100
2.573-2.66490.31391600.26313911X-RAY DIFFRACTION100
2.6649-2.77160.30271290.25423937X-RAY DIFFRACTION100
2.7716-2.89770.3011570.24933879X-RAY DIFFRACTION100
2.8977-3.05050.28591500.2353920X-RAY DIFFRACTION100
3.0505-3.24160.26171400.22513962X-RAY DIFFRACTION100
3.2416-3.49180.25661480.21473917X-RAY DIFFRACTION99
3.4918-3.8430.21461440.18793912X-RAY DIFFRACTION99
3.843-4.39870.21571440.17453942X-RAY DIFFRACTION99
4.3987-5.54060.19511380.17223954X-RAY DIFFRACTION99
5.5406-47.01390.25161620.19324003X-RAY DIFFRACTION99
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)Origin x (Å)Origin y (Å)Origin z (Å)
10.5411-0.21570.54991.1908-0.01630.447-0.0323-0.4081-0.13430.21340.0170.09840.0582-0.2308-0.68820.4782-0.0146-0.00880.44660.18130.377822.41654.23199.5704
20.53320.16140.06490.25550.03250.1594-0.2070.1748-0.64540.15220.02060.1770.17250.0615-0.07980.54850.07240.07050.39850.03440.792827.1203-10.78980.8564
30.5670.0189-0.22950.9633-0.63480.84150.03920.1102-0.2358-0.1679-0.2229-0.14050.1486-0.0342-0.01760.28850.03480.01510.22770.03260.321531.313811.8302-10.1246
40.2831-0.2071-0.21260.3987-0.09470.3740.1041-0.1743-0.04170.3053-0.154-0.50180.01220.28090.06340.50670.0728-0.14330.45530.19040.575538.03433.72522.6847
50.966-0.6440.0740.7112-0.27620.3991-0.1218-0.39240.45110.23660.1054-0.63770.0080.10190.00410.37-0.0248-0.1110.3702-0.04680.553232.64830.74.5812
60.4279-0.28870.0470.3918-0.02680.5909-0.2021-0.24940.08870.20370.1971-0.2530.08890.2206-0.00540.4540.0571-0.15560.5323-0.07370.413428.570526.627413.5265
71.5029-0.98590.07561.17550.10060.2481-0.3457-0.42210.31390.33410.2788-0.0174-0.1138-0.1411-0.02310.48240.12970.00650.5267-0.03240.29451.265937.178312.4071
80.9717-0.8418-0.3860.61360.23290.2916-0.17360.0861-0.07420.0547-0.09220.1380.0256-0.2637-0.00550.34230.0215-0.00430.51690.01950.31723.87826.35961.7669
91.04840.531-0.71080.8153-0.31510.3995-0.1086-0.0452-0.312-0.1567-0.0942-0.32020.2074-0.0509-0.00030.5370.0177-0.02360.4277-0.02930.5251.643-5.342549.843
100.67390.2907-0.30561.2554-0.01430.6242-0.00540.2197-0.3323-0.22960.2574-0.5471-0.04580.12630.00090.4216-0.03970.06960.5614-0.20220.693612.41757.723440.4951
110.6909-0.0891-0.08290.6673-0.21130.62090.0889-0.02480.1619-0.05390.146-0.3428-0.07870.11600.4451-0.06770.080.4301-0.08190.55327.959129.885852.5097
121.7636-0.3321-0.11810.55660.00150.08610.10960.00230.2149-0.05810.03030.0043-0.1277-0.0957-00.45680.06440.03580.4070.0650.3757-20.68736.207254.6571
130.32030.0578-0.16640.3261-0.03140.08090.0650.0339-0.0987-0.12770.1352-0.01870.0319-0.2666-00.39380.0351-0.04430.4670.04460.3706-17.205428.815448.7067
140.3924-0.03220.1980.2260.17350.23870.11320.3552-0.37150.0238-0.01720.07940.002-0.2314-0.00240.417500.00210.53750.01860.3708-17.251622.072944.1374
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 1108 through 1150 )
2X-RAY DIFFRACTION2chain 'A' and (resid 1151 through 1222 )
3X-RAY DIFFRACTION3chain 'A' and (resid 1223 through 1335 )
4X-RAY DIFFRACTION4chain 'A' and (resid 1336 through 1373 )
5X-RAY DIFFRACTION5chain 'A' and (resid 1374 through 1474 )
6X-RAY DIFFRACTION6chain 'A' and (resid 1475 through 1522 )
7X-RAY DIFFRACTION7chain 'A' and (resid 1877 through 2050 )
8X-RAY DIFFRACTION8chain 'A' and (resid 2051 through 2113 )
9X-RAY DIFFRACTION9chain 'C' and (resid 1108 through 1222 )
10X-RAY DIFFRACTION10chain 'C' and (resid 1223 through 1393 )
11X-RAY DIFFRACTION11chain 'C' and (resid 1394 through 1522 )
12X-RAY DIFFRACTION12chain 'C' and (resid 1877 through 2050 )
13X-RAY DIFFRACTION13chain 'C' and (resid 2051 through 2070 )
14X-RAY DIFFRACTION14chain 'C' and (resid 2071 through 2114 )

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