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- PDB-5lz4: Fragment-based inhibitors of Lipoprotein associated Phospholipase A2 -

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Basic information

Entry
Database: PDB / ID: 5lz4
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 / platelet activating factor metabolic process / calcium-independent phospholipase A2 activity / 1-alkyl-2-acetylglycerophosphocholine esterase activity / 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 / platelet activating factor metabolic process / calcium-independent phospholipase A2 activity / 1-alkyl-2-acetylglycerophosphocholine esterase activity / lipid oxidation / low-density lipoprotein particle / high-density lipoprotein particle / low-density lipoprotein particle remodeling / positive regulation of monocyte chemotaxis / hydrolase activity, acting on ester bonds / phosphatidylcholine catabolic process / peptide hormone processing / 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-7BW / Platelet-activating factor acetylhydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.07 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 2.0May 8, 2024Group: Atomic model / Data collection / Database references
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2
Item: _atom_site.occupancy / _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)44,5504
Polymers44,2031
Non-polymers3473
Water6,954386
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint-17 kcal/mol
Surface area15600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.935, 90.948, 51.340
Angle α, β, γ (deg.)90.00, 111.86, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-602-

HOH

21A-920-

HOH

31A-941-

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 I429H, insertion 429HHHH
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLA2G7, PAFAH / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
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-7BW / 5-[2-(4,4-dimethyl-2-oxidanylidene-pyrrolidin-1-yl)ethoxy]-2-fluoranyl-benzenecarbonitrile


Mass: 276.306 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H17FN2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 386 / 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: 49.78 %
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: Mar 15, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.07→45.47 Å / Num. obs: 26172 / % possible obs: 96.2 % / Redundancy: 2.5 % / Rmerge(I) obs: 0.038 / Net I/σ(I): 17
Reflection shellResolution: 2.07→2.12 Å / Rmerge(I) obs: 0.14 / Mean I/σ(I) obs: 6.8 / % possible all: 90.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.07→45.47 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.93 / SU B: 7.65 / SU ML: 0.116 / Cross valid method: THROUGHOUT / ESU R: 0.198 / ESU R Free: 0.173 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21491 1284 5.1 %RANDOM
Rwork0.16116 ---
obs0.16389 23972 96.49 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 28.141 Å2
Baniso -1Baniso -2Baniso -3
1--0.96 Å20 Å2-0.04 Å2
2--1.5 Å2-0 Å2
3----0.37 Å2
Refinement stepCycle: 1 / Resolution: 2.07→45.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2978 0 22 386 3386
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0193129
X-RAY DIFFRACTIONr_bond_other_d0.0020.022967
X-RAY DIFFRACTIONr_angle_refined_deg1.4551.9464249
X-RAY DIFFRACTIONr_angle_other_deg1.1192.9876840
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5395389
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.12623.747150
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.22315.027547
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8521518
X-RAY DIFFRACTIONr_chiral_restr0.0890.2455
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.0213562
X-RAY DIFFRACTIONr_gen_planes_other00.02753
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_it0.9092.9371509
X-RAY DIFFRACTIONr_mcbond_other0.9072.9351508
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.1163.231620
X-RAY DIFFRACTIONr_scbond_other1.1163.2311621
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined2.2836.7041106
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: 2.066→2.12 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.225 76 -
Rwork0.176 1657 -
obs--88.83 %
Refinement TLS params.Method: refined / Origin x: 30.4898 Å / Origin y: 14.6393 Å / Origin z: 0.8151 Å
111213212223313233
T0.0014 Å20.0071 Å2-0.0033 Å2-0.0861 Å2-0.0348 Å2--0.0178 Å2
L2.0893 °2-0.0419 °20.1615 °2-1.6784 °2-0.3426 °2--2.0316 °2
S0.0365 Å °-0.0043 Å °0.0178 Å °-0.0125 Å °-0.0476 Å °0.0821 Å °-0.0089 Å °0.066 Å °0.0111 Å °

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