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- PDB-5ye8: The crystal structure of Lp-PLA2 in complex with a novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 5ye8
TitleThe crystal structure of Lp-PLA2 in complex with a novel inhibitor
ComponentsPlatelet-activating factor acetylhydrolase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / hydrolase inhibitor / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


plasma lipoprotein particle oxidation / platelet activating factor catabolic process / 1-alkyl-2-acetylglycerophosphocholine esterase / calcium-independent phospholipase A2 activity / 1-alkyl-2-acetylglycerophosphocholine esterase activity / platelet activating factor metabolic process / lipid oxidation / low-density lipoprotein particle / high-density lipoprotein particle / low-density lipoprotein particle remodeling ...plasma lipoprotein particle oxidation / platelet activating factor catabolic process / 1-alkyl-2-acetylglycerophosphocholine esterase / calcium-independent phospholipase A2 activity / 1-alkyl-2-acetylglycerophosphocholine esterase activity / platelet activating factor metabolic process / lipid oxidation / low-density lipoprotein particle / high-density lipoprotein particle / low-density lipoprotein particle remodeling / positive regulation of monocyte chemotaxis / phosphatidylcholine catabolic process / peptide hormone processing / hydrolase activity, acting on ester bonds / Synthesis, secretion, and deacylation of Ghrelin / phospholipid binding / positive regulation of inflammatory response / extracellular region
Similarity search - Function
Platelet-activating factor acetylhydrolase, eucaryote / Platelet-activating factor acetylhydrolase, isoform II / Lipases, serine active site. / Alpha/Beta hydrolase fold, catalytic domain / Alpha/Beta hydrolase fold / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
N-[3,4-bis(fluoranyl)phenyl]methanesulfonamide / Platelet-activating factor acetylhydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.851 Å
AuthorsLiu, Q.F. / Xu, Y.C.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2.
Authors: Liu, Q. / Huang, F. / Yuan, X. / Wang, K. / Zou, Y. / Shen, J. / Xu, Y.
History
DepositionSep 15, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 25, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Platelet-activating factor acetylhydrolase
A: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)88,2264
Polymers87,8122
Non-polymers4142
Water5,278293
1
A: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,1132
Polymers43,9061
Non-polymers2071
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,1132
Polymers43,9061
Non-polymers2071
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)115.869, 82.772, 96.655
Angle α, β, γ (deg.)90.000, 115.250, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-633-

HOH

21B-721-

HOH

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Components

#1: Protein Platelet-activating factor acetylhydrolase / Lp-PLA2 / PAF acetylhydrolase / 1-alkyl-2-acetylglycerophosphocholine esterase / 2-acetyl-1- ...Lp-PLA2 / PAF acetylhydrolase / 1-alkyl-2-acetylglycerophosphocholine esterase / 2-acetyl-1-alkylglycerophosphocholine esterase / Group-VIIA phospholipase A2 / gVIIA-PLA2 / LDL-associated phospholipase A2 / LDL-PLA(2) / PAF 2-acylhydrolase


Mass: 43905.816 Da / Num. of mol.: 2 / Fragment: UNP residues 47-429
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLA2G7, PAFAH / Production host: Escherichia coli (E. coli)
References: UniProt: Q13093, 1-alkyl-2-acetylglycerophosphocholine esterase
#2: Chemical ChemComp-8U3 / N-[3,4-bis(fluoranyl)phenyl]methanesulfonamide


Mass: 207.198 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H7F2NO2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 293 / 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: 2.39 Å3/Da / Density % sol: 48.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M MOPS pH 6.6, 0.4M Li2SO4, 27% (w/v) (NH4)2SO4, 1M Na-Ac, 1.4% 1,4-butanediol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.9798 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Dec 6, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9798 Å / Relative weight: 1
ReflectionResolution: 1.85→50 Å / Num. obs: 69022 / % possible obs: 98.4 % / Redundancy: 6.5 % / Biso Wilson estimate: 18.35 Å2 / Rmerge(I) obs: 0.085 / Rpim(I) all: 0.035 / Rrim(I) all: 0.092 / Χ2: 0.907 / Net I/σ(I): 7.5 / Num. measured all: 449717
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.85-1.884.61.0733410.6340.5321.2010.74595.2
1.88-1.925.80.96934440.7290.4321.0640.75699
1.92-1.956.20.79534510.8040.3430.8680.75498.7
1.95-1.996.40.69734300.8320.2970.7590.77999
1.99-2.046.60.5934780.890.2460.640.81198.8
2.04-2.086.60.47234520.9360.1970.5130.82198.8
2.08-2.146.70.40434120.9420.1680.4380.87598.8
2.14-2.196.60.3434390.9570.1410.3690.94698.6
2.19-2.266.60.29434430.9630.1230.320.9698.7
2.26-2.336.30.25934300.9640.1110.2830.96598.1
2.33-2.415.90.21933900.9730.0970.241.10196.3
2.41-2.517.10.1934990.9820.0760.2051.02599.5
2.51-2.637.10.15734660.9880.0630.1691.05499.4
2.63-2.767.10.13134750.9890.0530.1421.10299.2
2.76-2.9470.10734730.9920.0430.1151.08299
2.94-3.166.90.08534600.9940.0340.0911.05498.4
3.16-3.486.10.0733810.9940.030.0771.0496.1
3.48-3.9970.05735040.9960.0230.0620.87499.5
3.99-5.026.90.05135190.9960.0210.0550.73799.3
5.02-506.60.04635350.9980.0190.050.56597.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation1.85 Å46.58 Å
Translation5.93 Å46.58 Å

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.9_1692)refinement
HKL-3000data collection
HKL-3000data scaling
PDB_EXTRACT3.22data extraction
HKL-3000data reduction
HKL-3000phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I8P

5i8p


Resolution: 1.851→41.733 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.52 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2119 3023 4.99 %
Rwork0.1806 57556 -
obs0.1822 60579 86.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 59.64 Å2 / Biso mean: 20.2874 Å2 / Biso min: 6.03 Å2
Refinement stepCycle: final / Resolution: 1.851→41.733 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5673 0 26 293 5992
Biso mean--17.2 25.85 -
Num. residues----734
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075838
X-RAY DIFFRACTIONf_angle_d1.0387920
X-RAY DIFFRACTIONf_chiral_restr0.044865
X-RAY DIFFRACTIONf_plane_restr0.0051018
X-RAY DIFFRACTIONf_dihedral_angle_d12.7732058
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 22

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8515-1.88040.2669320.219971174323
1.8804-1.91120.3179540.22731125117937
1.9112-1.94420.2524650.21411460152548
1.9442-1.97950.25451040.21521771187558
1.9795-2.01760.27571210.21252166228771
2.0176-2.05880.24591310.19752551268286
2.0588-2.10360.25151320.19662908304095
2.1036-2.15250.23561570.18592939309697
2.1525-2.20630.22951510.18652946309798
2.2063-2.2660.23071690.18282980314999
2.266-2.33260.26411440.18342982312698
2.3326-2.40790.22541490.18092924307396
2.4079-2.4940.21371640.17843005316999
2.494-2.59380.23061700.18643012318299
2.5938-2.71180.21591550.193012316799
2.7118-2.85480.2361660.19013002316899
2.8548-3.03360.24821600.19033001316199
3.0336-3.26770.2261600.18832975313598
3.2677-3.59640.20051500.16992957310797
3.5964-4.11640.15991730.154730253198100
4.1164-5.18470.16481430.15223060320399
5.1847-41.74350.19161730.19113044321798

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