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

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Basic information

Entry
Database: PDB / ID: 5lyy
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 / 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-7BJ / Platelet-activating factor acetylhydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.17 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)44,5092
Polymers44,2031
Non-polymers3061
Water4,179232
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area15470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.924, 91.157, 51.333
Angle α, β, γ (deg.)90.00, 111.88, 90.00
Int Tables number5
Space group name H-MC121

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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, I429H, insertion HHHH at C-terminal
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-7BJ / 3-[2-(4-fluoranylphenoxy)ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione


Mass: 306.332 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H19FN2O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 232 / 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: 49.88 %
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 RAXIS II / Detector: IMAGE PLATE / Date: Sep 17, 2010 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.17→34.38 Å / Num. obs: 22495 / % possible obs: 98.2 % / Redundancy: 2.3 % / Rmerge(I) obs: 0.062 / Net I/σ(I): 10.3
Reflection shellResolution: 2.17→2.31 Å / Rmerge(I) obs: 0.459 / Mean I/σ(I) obs: 1.9 / % possible all: 99.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
SCALAdata scaling
REFMAC5.8.0135phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.17→34.38 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.935 / SU B: 12.634 / SU ML: 0.164 / Cross valid method: THROUGHOUT / ESU R: 0.252 / ESU R Free: 0.197 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22523 1116 5.1 %RANDOM
Rwork0.1773 ---
obs0.17971 20933 97.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 40.016 Å2
Baniso -1Baniso -2Baniso -3
1-0.36 Å2-0 Å20.81 Å2
2---2.34 Å20 Å2
3---1 Å2
Refinement stepCycle: 1 / Resolution: 2.17→34.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2978 0 22 232 3232
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0193091
X-RAY DIFFRACTIONr_bond_other_d0.0020.022925
X-RAY DIFFRACTIONr_angle_refined_deg1.4321.9444186
X-RAY DIFFRACTIONr_angle_other_deg0.9362.9856738
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6155376
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.42923.47151
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.35415.028541
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.3331518
X-RAY DIFFRACTIONr_chiral_restr0.0830.2446
X-RAY DIFFRACTIONr_gen_planes_refined00.0213498
X-RAY DIFFRACTIONr_gen_planes_other00.02744
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_it1.2253.6911489
X-RAY DIFFRACTIONr_mcbond_other1.2253.6861488
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.8444.2291601
X-RAY DIFFRACTIONr_scbond_other1.8434.2311602
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.7578.7351087
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: 2.174→2.23 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 83 -
Rwork0.277 1555 -
obs--99.7 %
Refinement TLS params.Method: refined / Origin x: 30.4914 Å / Origin y: 14.6763 Å / Origin z: 0.801 Å
111213212223313233
T0.0101 Å20.0062 Å2-0.0236 Å2-0.2945 Å2-0.0399 Å2--0.0759 Å2
L2.4433 °2-0.1845 °20.2965 °2-1.8346 °2-0.3053 °2--2.0618 °2
S0.0418 Å °0.0339 Å °0.0262 Å °0.0009 Å °-0.0264 Å °0.1091 Å °-0.0301 Å °0.0199 Å °-0.0154 Å °

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