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

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Basic information

Entry
Database: PDB / ID: 5yea
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
Chem-8U9 / Platelet-activating factor acetylhydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.805 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
A: Platelet-activating factor acetylhydrolase
B: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,0947
Polymers87,8122
Non-polymers1,2825
Water7,116395
1
A: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5954
Polymers43,9061
Non-polymers6893
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14330 Å2
MethodPISA
2
B: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4993
Polymers43,9061
Non-polymers5932
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint-12 kcal/mol
Surface area14150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.791, 83.408, 96.889
Angle α, β, γ (deg.)90.000, 114.570, 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-8U9 / 4-[[4-[4-chloranyl-3-(trifluoromethyl)phenoxy]-3-cyano-phenyl]sulfamoyl]benzoic acid


Mass: 496.844 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H12ClF3N2O5S
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 395 / 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: 2.42 Å3/Da / Density % sol: 49.23 %
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: BL17U1 / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 10, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 75281 / % possible obs: 98.3 % / Redundancy: 6.8 % / Biso Wilson estimate: 19.55 Å2 / Rmerge(I) obs: 0.163 / Rpim(I) all: 0.066 / Rrim(I) all: 0.176 / Χ2: 0.96 / Net I/σ(I): 5.6 / Num. measured all: 513403
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.8-1.836.71.96137900.5590.8092.1250.78899.6
1.83-1.866.71.64438220.6270.6771.7810.81899.5
1.86-1.96.81.40437530.7040.5771.520.83899.1
1.9-1.946.81.04237690.7050.4281.1290.85398.9
1.94-1.986.80.86737700.8260.3530.9370.88598.5
1.98-2.036.80.73237360.8630.2980.7920.89898.2
2.03-2.086.80.61837270.8980.2520.6690.91998.1
2.08-2.136.80.52337060.9190.2130.5660.95397.7
2.13-2.26.90.45837310.9450.1860.4950.95497
2.2-2.276.90.41236630.9470.1670.4460.98596.7
2.27-2.356.80.37537350.9590.1520.4060.96796.5
2.35-2.446.80.30836630.9710.1250.3320.98196
2.44-2.556.80.27737010.9740.1120.2991.0296.9
2.55-2.696.80.2337110.9840.0930.2491.04297.1
2.69-2.866.70.18537540.9860.0750.21.09197.9
2.86-3.086.70.14137950.9910.0580.1521.11198.8
3.08-3.396.70.10738260.9940.0440.1161.19199.4
3.39-3.886.80.07738310.9950.0320.0831.11799.9
3.88-4.887.10.05638690.9980.0230.060.92999.9
4.88-507.30.05939290.9960.0240.0630.88499.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
HKL-2000data collection
HKL-2000data scaling
PHENIX(1.11.1_2575: ???)refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I8P

5i8p


Resolution: 1.805→37.695 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 20.66
RfactorNum. reflection% reflection
Rfree0.2111 3564 4.93 %
Rwork0.1769 --
obs0.1786 72308 93.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 60 Å2 / Biso mean: 21.0212 Å2 / Biso min: 8.47 Å2
Refinement stepCycle: final / Resolution: 1.805→37.695 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5754 0 81 395 6230
Biso mean--23.19 27.27 -
Num. residues----743
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095979
X-RAY DIFFRACTIONf_angle_d0.9528125
X-RAY DIFFRACTIONf_chiral_restr0.055878
X-RAY DIFFRACTIONf_plane_restr0.0061043
X-RAY DIFFRACTIONf_dihedral_angle_d7.3833519
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 25

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8047-1.82940.2849770.2661586166353
1.8294-1.85560.30121180.23952171228976
1.8556-1.88320.27641260.22462406253282
1.8832-1.91270.26271510.21722588273990
1.9127-1.9440.25011430.20242700284393
1.944-1.97760.26421390.19492808294795
1.9776-2.01350.21011320.19032783291596
2.0135-2.05220.21121540.192816297096
2.0522-2.09410.2161440.18082850299497
2.0941-2.13970.23431350.17422852298798
2.1397-2.18940.19381410.17222831297297
2.1894-2.24420.20551410.17112845298697
2.2442-2.30480.19811480.17682830297897
2.3048-2.37260.21051420.18082820296296
2.3726-2.44920.22881400.17592786292696
2.4492-2.53670.20091430.18212865300897
2.5367-2.63830.21191600.18342820298097
2.6383-2.75830.22461470.18072869301698
2.7583-2.90370.22781560.18522857301398
2.9037-3.08550.22481660.18112885305199
3.0855-3.32360.21331530.18272911306499
3.3236-3.65790.16991420.163829403082100
3.6579-4.18660.19361520.152629563108100
4.1866-5.27230.17921510.154429583109100
5.2723-37.70370.21871630.179430113174100

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