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- PDB-5ye7: The crystal structure of Lp-PLA2 in complex with a novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 5ye7
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 / platelet activating factor metabolic process / 1-alkyl-2-acetylglycerophosphocholine esterase activity / phosphatidylcholine catabolic process / lipid oxidation / low-density lipoprotein particle / high-density lipoprotein particle ...plasma lipoprotein particle oxidation / platelet activating factor catabolic process / 1-alkyl-2-acetylglycerophosphocholine esterase / calcium-independent phospholipase A2 activity / platelet activating factor metabolic process / 1-alkyl-2-acetylglycerophosphocholine esterase activity / phosphatidylcholine catabolic process / lipid oxidation / low-density lipoprotein particle / high-density lipoprotein particle / low-density lipoprotein particle remodeling / positive regulation of monocyte chemotaxis / 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
Chem-8U0 / Platelet-activating factor acetylhydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.312 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

Downloads & links

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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)88,8696
Polymers87,8122
Non-polymers1,0574
Water93752
1
A: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4343
Polymers43,9061
Non-polymers5292
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14150 Å2
MethodPISA
2
B: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4343
Polymers43,9061
Non-polymers5292
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-12 kcal/mol
Surface area14220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.830, 83.426, 96.760
Angle α, β, γ (deg.)90.000, 114.950, 90.000
Int Tables number5
Space group name H-MC121

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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-8U0 / N-[4-[(4-naphthalen-2-yloxyphenyl)sulfamoyl]phenyl]ethanamide


Mass: 432.492 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H20N2O4S
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 52 / 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: 2.41 Å3/Da / Density % sol: 49.04 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.6
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: BL17U1 / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 14, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. obs: 36097 / % possible obs: 99.7 % / Redundancy: 3.6 % / Biso Wilson estimate: 33.45 Å2 / Rmerge(I) obs: 0.162 / Rpim(I) all: 0.099 / Rrim(I) all: 0.19 / Χ2: 0.916 / Net I/σ(I): 5 / Num. measured all: 130789
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.3-2.343.60.97618030.5360.5921.1440.86899.8
2.34-2.383.60.85917750.6170.5251.0090.8899.8
2.38-2.433.60.82817980.6610.5040.9710.88999.9
2.43-2.483.60.79617940.6660.4830.9330.89399.8
2.48-2.533.60.69317950.6980.4210.8130.87599.7
2.53-2.593.60.62817790.7270.3810.7360.91499.8
2.59-2.663.70.54118110.7930.3280.6340.96299.8
2.66-2.733.70.47218190.820.2850.5520.92199.7
2.73-2.813.70.39617900.8560.240.4640.93399.7
2.81-2.93.70.32417790.8950.1960.3790.94799.8
2.9-33.70.26918110.9230.1620.3150.95199.6
3-3.123.70.21918060.9430.1320.2560.99999.9
3.12-3.263.70.18718060.9580.1130.2191.0199.8
3.26-3.443.60.14418070.9720.0880.171.11899.8
3.44-3.653.60.11317960.9790.0690.1331.08199.7
3.65-3.933.60.09218400.9850.0570.1081.03599.5
3.93-4.333.50.07417690.9870.0460.0880.93599.1
4.33-4.953.40.0618200.990.0380.0710.80199.6
4.95-6.243.70.06118350.9910.0370.0710.70799.7
6.24-503.60.04718640.9940.030.0560.61399.1

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I8P

5i8p


Resolution: 2.312→43.865 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.01 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2443 1679 4.9 %
Rwork0.1807 32617 -
obs0.1837 34296 93.47 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 75.74 Å2 / Biso mean: 33.4991 Å2 / Biso min: 15.4 Å2
Refinement stepCycle: final / Resolution: 2.312→43.865 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5700 0 72 52 5824
Biso mean--46.75 30.31 -
Num. residues----736
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075917
X-RAY DIFFRACTIONf_angle_d0.8848034
X-RAY DIFFRACTIONf_chiral_restr0.052870
X-RAY DIFFRACTIONf_plane_restr0.0061032
X-RAY DIFFRACTIONf_dihedral_angle_d7.7763444
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3115-2.37950.3061950.23751536163153
2.3795-2.45630.30841200.22852376249682
2.4563-2.54410.28211350.22212637277292
2.5441-2.64590.27821410.22132835297698
2.6459-2.76640.29961720.20922848302099
2.7664-2.91220.28921430.206828813024100
2.9122-3.09460.28821640.198629033067100
3.0946-3.33340.27081500.190228713021100
3.3334-3.66870.21751430.169929193062100
3.6687-4.19930.21511280.15672932306099
4.1993-5.28920.20051410.14822907304899
5.2892-43.87250.20921470.1722972311999

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