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- PDB-5i9i: Crystal structure of LP_PLA2 in complex with Darapladib -

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Basic information

Entry
Database: PDB / ID: 5i9i
TitleCrystal structure of LP_PLA2 in complex with Darapladib
ComponentsPlatelet-activating factor acetylhydrolase1-alkyl-2-acetylglycerophosphocholine esterase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Lp_pla2 inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


plasma lipoprotein particle oxidation / platelet activating factor catabolic process / calcium-independent phospholipase A2 activity / 1-alkyl-2-acetylglycerophosphocholine esterase / platelet activating factor metabolic process / 1-alkyl-2-acetylglycerophosphocholine esterase activity / lipid oxidation / phosphatidylcholine catabolic process / low-density lipoprotein particle / high-density lipoprotein particle ...plasma lipoprotein particle oxidation / platelet activating factor catabolic process / calcium-independent phospholipase A2 activity / 1-alkyl-2-acetylglycerophosphocholine esterase / platelet activating factor metabolic process / 1-alkyl-2-acetylglycerophosphocholine esterase activity / lipid oxidation / phosphatidylcholine catabolic process / 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-5HV / Platelet-activating factor acetylhydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.7 Å
AuthorsLiu, Q.F. / Xu, Y.C.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Structural and Thermodynamic Characterization of Protein-Ligand Interactions Formed between Lipoprotein-Associated Phospholipase A2 and Inhibitors
Authors: Liu, Q.F. / Chen, X.D. / Chen, W.Y. / Yuan, X.J. / Su, H.X. / Shen, J.H. / Xu, Y.C.
History
DepositionFeb 20, 2016Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 15, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / citation / database_2 / entity / pdbx_entity_nonpoly / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _chem_comp.name / _citation.journal_id_CSD ..._chem_comp.name / _citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)89,3376
Polymers87,8122
Non-polymers1,5264
Water1086
1
A: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5732
Polymers43,9061
Non-polymers6671
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area110 Å2
ΔGint-8 kcal/mol
Surface area13930 Å2
MethodPISA
2
B: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,7654
Polymers43,9061
Non-polymers8593
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-8 kcal/mol
Surface area13720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.900, 82.410, 96.470
Angle α, β, γ (deg.)90.000, 115.500, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Platelet-activating factor acetylhydrolase / 1-alkyl-2-acetylglycerophosphocholine esterase / PAF acetylhydrolase / 1-alkyl-2-acetylglycerophosphocholine esterase / 2-acetyl-1- ...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 / Plasmid: pGEX-6P-1 / Production host: Escherichia coli (E. coli) / Strain (production host): Rosetta2 pLysS
References: UniProt: Q13093, 1-alkyl-2-acetylglycerophosphocholine esterase
#2: Chemical ChemComp-5HV / N-[2-(diethylamino)ethyl]-2-{2-[(4-fluorobenzyl)sulfanyl]-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl}-N-{[ 4'-(trifluoromethyl)biphenyl-4-yl]methyl}acetamide / Darapladib / Darapladib


Mass: 666.771 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C36H38F4N4O2S / Comment: inhibitor*YM
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 18.015 Da / Num. of mol.: 6 / 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: 2.37 Å3/Da / Density % sol: 48.06 %
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: BL17U / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Dec 15, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.7→44.064 Å / Num. obs: 22260 / % possible obs: 95.5 % / Observed criterion σ(I): -3 / Redundancy: 1.96 % / Biso Wilson estimate: 34.72 Å2 / CC1/2: 0.985 / Rmerge(I) obs: 0.094 / Net I/σ(I): 8.59
Reflection shell
Resolution (Å)Highest resolution (Å)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
2.7-2.770.3922.6196.9
2.77-2.850.3422.95196.3
2.85-2.930.2883.42197.4
2.93-3.020.2483.94197.2
3.02-3.120.2034.68196.3
3.12-3.230.1645.44197.4
3.23-3.350.1436.33196.6
3.35-3.490.1097.94195.1
3.49-3.640.0939.07195
3.64-3.820.07910.21194.9
3.82-4.020.0711.45193.9
4.02-4.270.06312.48193.7
4.27-4.560.0514.24192.6
4.56-4.930.04814.84190.5
4.93-5.40.04914.54195.3
5.4-6.040.05113.74195.2
6.04-6.970.04814.58196.3
6.97-8.540.03817.33194.2
8.54-12.070.0321.06193.6
12.070.02822.72193.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation7.09 Å44.07 Å
Translation7.09 Å44.07 Å

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XSCALEdata scaling
PHASER2.5.6model building
PDB_EXTRACT3.2data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3D59

3d59


Resolution: 2.7→44.064 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 0.93 / Phase error: 26.34
RfactorNum. reflection% reflection
Rfree0.2613 668 2.97 %
Rwork0.1909 --
obs0.193 22260 95.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 74.01 Å2 / Biso mean: 29.1156 Å2 / Biso min: 8.51 Å2
Refinement stepCycle: final / Resolution: 2.7→44.064 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5539 0 104 6 5649
Biso mean--35.15 20.86 -
Num. residues----734
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095789
X-RAY DIFFRACTIONf_angle_d1.2087884
X-RAY DIFFRACTIONf_chiral_restr0.046848
X-RAY DIFFRACTIONf_plane_restr0.0061021
X-RAY DIFFRACTIONf_dihedral_angle_d15.1921980
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.6999-2.8080.32161380.2544630476897
2.808-2.93580.38351410.23714654479597
2.9358-3.09050.30681440.22684668481297
3.0905-3.28410.2881440.21284597474197
3.2841-3.53760.28511400.1884564470496
3.5376-3.89340.2491350.16824523465895
3.8934-4.45630.18521400.16154483462394
4.4563-5.61260.23951380.16684438457694
5.6126-44.07030.25141400.19254559469995

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