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- PDB-5lz2: Fragment-based inhibitors of Lipoprotein associated Phospholipase A2 -

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Basic information

Entry
Database: PDB / ID: 5lz2
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
3-cyano-~{N}-cyclopropyl-benzenesulfonamide / 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 1.1Jul 13, 2022Group: Database references / Derived calculations / Structure summary
Category: audit_author / database_2 ...audit_author / database_2 / pdbx_struct_conn_angle / pdbx_struct_special_symmetry / struct_conn
Item: _audit_author.name / _database_2.pdbx_DOI ..._audit_author.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_symmetry
Revision 1.2Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,4844
Polymers44,2031
Non-polymers2813
Water6,287349
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area210 Å2
ΔGint-13 kcal/mol
Surface area15380 Å2
MethodPISA
Unit cell
Length a, b, c (Å)99.971, 90.649, 51.321
Angle α, β, γ (deg.)90.00, 111.82, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11A-501-

NA

21A-634-

HOH

31A-896-

HOH

41A-899-

HOH

51A-908-

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
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-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-7BX / 3-cyano-~{N}-cyclopropyl-benzenesulfonamide


Mass: 222.264 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H10N2O2S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 349 / 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: 2.44 Å3/Da / Density % sol: 49.63 %
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 IV / 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: 2.1→32.42 Å / Num. obs: 24963 / % possible obs: 97 % / Redundancy: 2.4 % / Rmerge(I) obs: 0.033 / Net I/σ(I): 21.5
Reflection shellResolution: 2.1→2.15 Å / Rmerge(I) obs: 0.125 / Mean I/σ(I) obs: 8.3 / % possible all: 90

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
XDSdata reduction
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.1→32.42 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.922 / SU B: 9.18 / SU ML: 0.133 / Cross valid method: THROUGHOUT / ESU R: 0.219 / ESU R Free: 0.189 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22783 1241 5.1 %RANDOM
Rwork0.16738 ---
obs0.17046 22980 96.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 27.191 Å2
Baniso -1Baniso -2Baniso -3
1--0.56 Å2-0 Å2-0.2 Å2
2--1.41 Å20 Å2
3----0.53 Å2
Refinement stepCycle: 1 / Resolution: 2.1→32.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2978 0 17 349 3344
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0193154
X-RAY DIFFRACTIONr_bond_other_d0.0020.022984
X-RAY DIFFRACTIONr_angle_refined_deg1.4431.9434288
X-RAY DIFFRACTIONr_angle_other_deg1.0932.9956886
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6215396
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.62824.118153
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.86315.081553
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.941518
X-RAY DIFFRACTIONr_chiral_restr0.0860.2459
X-RAY DIFFRACTIONr_gen_planes_refined00.023601
X-RAY DIFFRACTIONr_gen_planes_other00.02764
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_it0.792.421518
X-RAY DIFFRACTIONr_mcbond_other0.7892.4171517
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.0042.7061634
X-RAY DIFFRACTIONr_scbond_other1.0032.7071635
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined2.3225.5671119
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: 2.097→2.151 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.318 89 -
Rwork0.198 1474 -
obs--84.76 %
Refinement TLS params.Method: refined / Origin x: 30.4952 Å / Origin y: 14.6819 Å / Origin z: 0.8508 Å
111213212223313233
T0.0018 Å20.0117 Å2-0.0037 Å2-0.1679 Å2-0.038 Å2--0.0127 Å2
L1.9505 °2-0.0397 °20.1987 °2-1.6674 °2-0.2234 °2--1.7422 °2
S0.0255 Å °-0.0773 Å °0.0329 Å °-0.0222 Å °-0.0636 Å °0.082 Å °-0.0186 Å °-0.0079 Å °0.0382 Å °

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