[English] 日本語
Yorodumi
- PDB-5c37: Structure of the beta-ketoacyl reductase domain of human fatty ac... -

+
Open data


ID or keywords:

Loading...

-
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 / (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 / fatty acid synthase activity / [acyl-carrier-protein] S-malonyltransferase / [acyl-carrier-protein] S-malonyltransferase 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. / Acyl transferase/acyl hydrolase/lysophospholipase / Alcohol dehydrogenase-like, C-terminal / 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-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: to be published
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. / Smans, K. / Ludovici, D. / Parker, M. / Meyer, C. / Rocaboy, C. / Alexander, R. / Grasberger, B. / De Breucker, S. / ...Authors: Lu, T. / Schubert, C. / Cummings, M.D. / Bignan, G. / Connolly, P. / Smans, K. / Ludovici, D. / Parker, M. / 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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
Components

-
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

-
Non-polymers , 5 types, 243 molecules

#2: 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
#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 / Chloride


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 / Glycerol


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


Mass: 18.015 Da / Num. of mol.: 235 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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: 0

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

-
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 )

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more