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- PDB-6nna: Human Fatty Acid Synthase Psi/KR Tri-Domain with NADPH and Compound 22 -

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Basic information

Entry
Database: PDB / ID: 6nna
TitleHuman Fatty Acid Synthase Psi/KR Tri-Domain with NADPH and Compound 22
ComponentsFatty acid synthase,Fatty acid synthase
KeywordsTRANSFERASE / FATTY ACID SYNTHASE / HUMAN FAS / KETO-REDUCTASE
Function / homology
Function and homology information


fatty-acid synthase system / ether lipid biosynthetic process / Vitamin B5 (pantothenate) metabolism / neutrophil differentiation / [acyl-carrier-protein] S-acetyltransferase / enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific) / [acyl-carrier-protein] S-acetyltransferase activity / glandular epithelial cell development / enoyl-[acyl-carrier-protein] reductase (NADPH, A-specific) activity / oleoyl-[acyl-carrier-protein] hydrolase ...fatty-acid synthase system / ether lipid biosynthetic process / Vitamin B5 (pantothenate) metabolism / neutrophil differentiation / [acyl-carrier-protein] S-acetyltransferase / enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific) / [acyl-carrier-protein] S-acetyltransferase activity / glandular epithelial cell development / enoyl-[acyl-carrier-protein] reductase (NADPH, A-specific) activity / oleoyl-[acyl-carrier-protein] hydrolase / oleoyl-[acyl-carrier-protein] hydrolase activity / myristoyl-[acyl-carrier-protein] hydrolase activity / palmitoyl-[acyl-carrier-protein] hydrolase activity / fatty acid synthase activity / glycogen granule / Fatty acyl-CoA biosynthesis / establishment of endothelial intestinal barrier / ChREBP activates metabolic gene expression / [acyl-carrier-protein] S-malonyltransferase / [acyl-carrier-protein] S-malonyltransferase activity / modulation by host of viral process / 3-hydroxyacyl-[acyl-carrier-protein] dehydratase / (3R)-hydroxymyristoyl-[acyl-carrier-protein] dehydratase activity / (3R)-3-hydroxydecanoyl-[acyl-carrier-protein] dehydratase activity / (3R)-3-hydroxyoctanoyl-[acyl-carrier-protein] dehydratase activity / (3R)-hydroxypalmitoyl-[acyl-carrier-protein] dehydratase activity / beta-ketoacyl-[acyl-carrier-protein] synthase I / NR1H2 & NR1H3 regulate gene expression linked to lipogenesis / 3-oxoacyl-[acyl-carrier-protein] reductase / 3-oxoacyl-[acyl-carrier-protein] reductase (NADPH) activity / mammary gland development / phosphopantetheine binding / 3-oxoacyl-[acyl-carrier-protein] synthase activity / monocyte differentiation / 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
Methyltransferase type 12 / Methyltransferase domain / Thioesterase / Thioesterase domain / PKS_DH / Polyketide synthase, dehydratase domain superfamily / Polyketide synthase, dehydratase domain / Polyketide synthase dehydratase / Ketosynthase family 3 (KS3) domain profile. / Polyketide synthase, ketoreductase domain ...Methyltransferase type 12 / Methyltransferase domain / Thioesterase / Thioesterase domain / PKS_DH / Polyketide synthase, dehydratase domain superfamily / Polyketide synthase, dehydratase domain / Polyketide synthase dehydratase / Ketosynthase family 3 (KS3) domain profile. / Polyketide synthase, ketoreductase domain / KR domain / Malonyl-CoA ACP transacylase, ACP-binding / Polyketide synthase, C-terminal extension / Ketoacyl-synthetase C-terminal extension / 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 / Beta-ketoacyl synthase, active site / Ketosynthase family 3 (KS3) active site signature. / Polyketide synthase, beta-ketoacyl synthase domain / Beta-ketoacyl synthase / Polyketide synthase, enoylreductase domain / Enoylreductase / Polyketide synthase, phosphopantetheine-binding domain / Phosphopantetheine attachment site / 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 / NAD(P)-binding Rossmann-like Domain / S-adenosyl-L-methionine-dependent methyltransferase superfamily / NAD(P)-binding domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-KUA / Chem-NDP / Fatty acid synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.26 Å
AuthorsToms, A.V. / Martin, M.W.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2019
Title: Discovery and optimization of novel piperazines as potent inhibitors of fatty acid synthase (FASN).
Authors: Martin, M.W. / Lancia Jr., D.R. / Li, H. / Schiller, S.E.R. / Toms, A.V. / Wang, Z. / Bair, K.W. / Castro, J. / Fessler, S. / Gotur, D. / Hubbs, S.E. / Kauffman, G.S. / Kershaw, M. / Luke, G. ...Authors: Martin, M.W. / Lancia Jr., D.R. / Li, H. / Schiller, S.E.R. / Toms, A.V. / Wang, Z. / Bair, K.W. / Castro, J. / Fessler, S. / Gotur, D. / Hubbs, S.E. / Kauffman, G.S. / Kershaw, M. / Luke, G.P. / McKinnon, C. / Yao, L. / Lu, W. / Millan, D.S.
History
DepositionJan 14, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 20, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.pdbx_database_id_PubMed ..._citation.journal_abbrev / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Mar 20, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)147,01119
Polymers143,9302
Non-polymers3,08117
Water10,701594
1
A: Fatty acid synthase,Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,53610
Polymers71,9651
Non-polymers1,5719
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Fatty acid synthase,Fatty acid synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,4749
Polymers71,9651
Non-polymers1,5098
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.110, 85.740, 86.470
Angle α, β, γ (deg.)65.570, 90.000, 87.000
Int Tables number1
Space group name H-MP1

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Components

#1: Protein Fatty acid synthase,Fatty acid synthase


Mass: 71965.102 Da / Num. of mol.: 2 / Mutation: M1110Q,S1438A,P1524G,M1110Q,S1438A,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, [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
#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-KUA / {4-[4-(1,3-benzoxazol-2-yl)benzene-1-carbonyl]piperazin-1-yl}(1-hydroxycyclopropyl)methanone


Mass: 391.420 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H21N3O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 594 / 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: 45.48 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.6
Details: 0.19 M ammonium sulfate, 5 mM sodium cacodylate,pH7.6 and 27 % w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.97853 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 21, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 2.26→48.08 Å / Num. obs: 57291 / % possible obs: 97.3 % / Redundancy: 1.8 % / CC1/2: 0.988 / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.065 / Rrim(I) all: 0.093 / Net I/σ(I): 6.6
Reflection shellResolution: 2.26→2.32 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.344 / Num. unique obs: 4419 / CC1/2: 0.712 / Rpim(I) all: 0.344 / Rrim(I) all: 0.487 / % possible all: 96.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.7.3data scaling
PHASERphasing
REFMAC5.8.0238refinement
PDB_EXTRACT3.24data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4piv

4piv


Resolution: 2.26→48.08 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.899 / SU B: 7.655 / SU ML: 0.187 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.392 / ESU R Free: 0.25
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2508 2646 4.6 %RANDOM
Rwork0.2008 ---
obs0.2031 54645 97.34 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 123.42 Å2 / Biso mean: 34.873 Å2 / Biso min: 12.41 Å2
Baniso -1Baniso -2Baniso -3
1--0.52 Å20.65 Å2-0.27 Å2
2---0.47 Å20.23 Å2
3---0.91 Å2
Refinement stepCycle: final / Resolution: 2.26→48.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9280 0 206 594 10080
Biso mean--28.54 37.39 -
Num. residues----1216
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0139685
X-RAY DIFFRACTIONr_bond_other_d0.0010.0179112
X-RAY DIFFRACTIONr_angle_refined_deg1.3561.66213143
X-RAY DIFFRACTIONr_angle_other_deg1.1471.58421117
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.66951210
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.10321.792480
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.987151585
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.9511573
X-RAY DIFFRACTIONr_chiral_restr0.0540.21215
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0210755
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021976
LS refinement shellResolution: 2.26→2.319 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.352 163 -
Rwork0.285 4046 -
all-4209 -
obs--96.1 %

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