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- PDB-5lz5: Fragment-based inhibitors of Lipoprotein associated Phospholipase A2 -

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Basic information

Entry
Database: PDB / ID: 5lz5
TitleFragment-based inhibitors of Lipoprotein associated Phospholipase A2
ComponentsPlatelet-activating factor acetylhydrolase
KeywordsHYDROLASE / Lp-PLA2 phospholipase / lipid metabolism / inhibitors / Lp-PLA2#4
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-7K4 / Platelet-activating factor acetylhydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.05 Å
AuthorsWoolford, A.J.A. / Day, P.J.
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)44,6124
Polymers44,2031
Non-polymers4093
Water5,603311
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-17 kcal/mol
Surface area15450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)101.091, 91.494, 48.648
Angle α, β, γ (deg.)90.00, 111.92, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-610-

HOH

21A-863-

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 H429H, 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.: 2 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-7K4 / 2-fluoranyl-5-[2-[(4~{S})-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.: 311 / 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: 2.36 Å3/Da / Density % sol: 47.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.4
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 9, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.05→32.75 Å / Num. obs: 25783 / % possible obs: 97.7 % / Redundancy: 2.6 % / Rmerge(I) obs: 0.107 / Net I/σ(I): 8.9
Reflection shellResolution: 2.05→2.12 Å / Rmerge(I) obs: 0.6 / Mean I/σ(I) obs: 2.3 / % possible all: 87.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.05→32.75 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.92 / SU B: 12.035 / SU ML: 0.165 / Cross valid method: THROUGHOUT / ESU R: 0.218 / ESU R Free: 0.187 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23791 1298 5.1 %RANDOM
Rwork0.18356 ---
obs0.18637 23942 97.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 31.922 Å2
Baniso -1Baniso -2Baniso -3
1--1.13 Å2-0 Å21.13 Å2
2---1.41 Å20 Å2
3---1.23 Å2
Refinement stepCycle: 1 / Resolution: 2.05→32.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2978 0 27 311 3316
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0193127
X-RAY DIFFRACTIONr_bond_other_d0.0020.022954
X-RAY DIFFRACTIONr_angle_refined_deg1.4671.9444242
X-RAY DIFFRACTIONr_angle_other_deg1.2472.9866807
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7345384
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.65423.739153
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.86415.028543
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.191518
X-RAY DIFFRACTIONr_chiral_restr0.090.2452
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.0213548
X-RAY DIFFRACTIONr_gen_planes_other00.02759
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_it0.9674.1031497
X-RAY DIFFRACTIONr_mcbond_other0.9684.11496
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.2284.4321629
X-RAY DIFFRACTIONr_scbond_other1.2284.4331630
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined2.4089.2351101
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: 2.05→2.103 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.304 92 -
Rwork0.273 1502 -
obs--84.25 %
Refinement TLS params.Method: refined / Origin x: 31.0684 Å / Origin y: 14.6964 Å / Origin z: 0.9607 Å
111213212223313233
T0.0211 Å2-0.0044 Å20.0367 Å2-0.0064 Å2-0.0109 Å2--0.0802 Å2
L1.7624 °2-0.2888 °20.1339 °2-1.9162 °2-0.39 °2--1.4669 °2
S-0 Å °-0 Å °0.0232 Å °0.001 Å °-0.0018 Å °0.1607 Å °-0.0106 Å °-0.0842 Å °0.0019 Å °

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