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- PDB-5lz7: Fragment-based inhibitors of Lipoprotein associated Phospholipase A2 -

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Basic information

Entry
Database: PDB / ID: 5lz7
TitleFragment-based inhibitors of Lipoprotein associated Phospholipase A2
ComponentsPlatelet-activating factor acetylhydrolase
KeywordsHYDROLASE / Lp-PLA2 phospholipase / lipid metabolism / inhibitors
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-7BK / Platelet-activating factor acetylhydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsWoolford, A. / Day, P.
CitationJournal: J. Med. Chem. / Year: 2016
Title: Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2).
Authors: Woolford, A.J. / Day, P.J. / Beneton, V. / Berdini, V. / Coyle, J.E. / Dudit, Y. / Grondin, P. / Huet, P. / Lee, L.Y. / Manas, E.S. / McMenamin, R.L. / Murray, C.W. / Page, L.W. / Patel, V.K. ...Authors: Woolford, A.J. / Day, P.J. / Beneton, V. / Berdini, V. / Coyle, J.E. / Dudit, Y. / Grondin, P. / Huet, P. / Lee, L.Y. / Manas, E.S. / McMenamin, R.L. / Murray, C.W. / Page, L.W. / Patel, V.K. / Potvain, F. / Rich, S.J. / Sang, Y. / Somers, D.O. / Trottet, L. / Wan, Z. / Zhang, X.
History
DepositionSep 29, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 21, 2016Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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
A: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,5773
Polymers44,2031
Non-polymers3742
Water5,927329
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area100 Å2
ΔGint-7 kcal/mol
Surface area15690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.623, 91.456, 51.413
Angle α, β, γ (deg.)90.00, 112.11, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-602-

HOH

21A-865-

HOH

31A-893-

HOH

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Components

#1: Protein Platelet-activating factor acetylhydrolase / 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: 44203.129 Da / Num. of mol.: 1
Mutation: Deletion 1-45, deletion 430-442, substitution H429I, insertion 429HHHH
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLA2G7, PAFAH / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q13093, 1-alkyl-2-acetylglycerophosphocholine esterase
#2: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-7BK / 2-fluoranyl-5-[2-[(4~{R})-4-methyl-2-oxidanylidene-4-phenyl-pyrrolidin-1-yl]ethoxy]benzenecarbonitrile


Mass: 338.375 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H19FN2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 329 / 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: 2.45 Å3/Da / Density % sol: 49.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 28.0%w/v PEG 3350, 0.1M HEPES/NaOHpH=7.4, 1.3M NaCl

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Jun 12, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→32.99 Å / Num. obs: 25098 / % possible obs: 98.1 % / Redundancy: 3.6 % / Rmerge(I) obs: 0.085 / Net I/σ(I): 10.8
Reflection shellResolution: 2.1→2.18 Å / Rmerge(I) obs: 0.629 / Mean I/σ(I) obs: 2.2 / % possible all: 91.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
SCALAdata scaling
REFMAC5.8.0135phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.1→32.99 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.933 / SU B: 11.971 / SU ML: 0.168 / Cross valid method: THROUGHOUT / ESU R: 0.224 / ESU R Free: 0.197 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24251 1259 5.1 %RANDOM
Rwork0.18042 ---
obs0.18359 23429 98.22 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 42.578 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å2-0 Å20.79 Å2
2---0.55 Å20 Å2
3----0.08 Å2
Refinement stepCycle: 1 / Resolution: 2.1→32.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2978 0 26 329 3333
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0193098
X-RAY DIFFRACTIONr_bond_other_d0.0020.022928
X-RAY DIFFRACTIONr_angle_refined_deg1.4691.9474197
X-RAY DIFFRACTIONr_angle_other_deg1.2022.9866744
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6045378
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.56423.705149
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.48115.028538
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5121518
X-RAY DIFFRACTIONr_chiral_restr0.0860.2448
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.0213507
X-RAY DIFFRACTIONr_gen_planes_other00.02748
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.4465.5291491
X-RAY DIFFRACTIONr_mcbond_other1.4465.5261490
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.785.9161606
X-RAY DIFFRACTIONr_scbond_other1.7795.9181607
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined3.37612.3871086
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.096→2.15 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.347 86 -
Rwork0.275 1539 -
obs--87.13 %
Refinement TLS params.Method: refined / Origin x: 30.3517 Å / Origin y: 14.6329 Å / Origin z: 0.7993 Å
111213212223313233
T0.008 Å20.0039 Å20.0016 Å2-0.0491 Å2-0.0238 Å2--0.0252 Å2
L3.3302 °2-0.3787 °20.2878 °2-2.0706 °2-0.4603 °2--2.4216 °2
S0.1134 Å °-0.0061 Å °0.0379 Å °0.0021 Å °-0.0599 Å °0.1855 Å °-0.0848 Å °0.0108 Å °-0.0535 Å °

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