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- PDB-6m08: Crystal structure of Lp-PLA2 in complex with a novel covalent inh... -

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Basic information

Entry
Database: PDB / ID: 6m08
TitleCrystal structure of Lp-PLA2 in complex with a novel covalent inhibitor.
ComponentsPlatelet-activating factor acetylhydrolase
KeywordsHYDROLASE / Lp-PLA2 / Covalent inhibitor / Complex structure / Serine phospholipase.
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
Similarity search - Domain/homology
Chem-BWL / Platelet-activating factor acetylhydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.19 Å
AuthorsHu, H.C. / Xu, Y.C.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: J.Med.Chem. / Year: 2020
Title: Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach.
Authors: Huang, F. / Hu, H. / Wang, K. / Peng, C. / Xu, W. / Zhang, Y. / Gao, J. / Liu, Y. / Zhou, H. / Huang, R. / Li, M. / Shen, J. / Xu, Y.
History
DepositionFeb 20, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 30, 2020Provider: repository / Type: Initial release
Revision 2.0Jan 13, 2021Group: Advisory / Derived calculations ...Advisory / Derived calculations / Non-polymer description / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_entity_nonpoly / pdbx_validate_close_contact / struct_conn
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _entity.formula_weight / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Revision 2.1Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.2Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Platelet-activating factor acetylhydrolase
B: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)85,0683
Polymers84,5342
Non-polymers5341
Water1,06359
1
A: Platelet-activating factor acetylhydrolase


Theoretical massNumber of molelcules
Total (without water)42,2671
Polymers42,2671
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,8012
Polymers42,2671
Non-polymers5341
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)116.346, 82.345, 96.664
Angle α, β, γ (deg.)90.000, 115.730, 90.000
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: 42267.062 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLA2G7, PAFAH / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3)
References: UniProt: Q13093, 1-alkyl-2-acetylglycerophosphocholine esterase
#2: Chemical ChemComp-BWL / (2S)-2-[(Z)-3-[2-(diethylamino)ethyl-[[4-[4-(trifluoromethyl)phenyl]phenyl]methyl]amino]-1-oxidanyl-3-oxidanylidene-prop-1-enyl]pyrrolidine-1-carboxylic acid


Mass: 533.582 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H34F3N3O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 59 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.47 Å3/Da / Density % sol: 50.15 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1 M MOPS pH 6.6, 0.4 M Li2SO4, 22.5-27% (w/v) (NH4)2SO4, 1 M Na-Ac, 1.4 % 1,4-butanediol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 24, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.19→50 Å / Num. obs: 42102 / % possible obs: 99.6 % / Redundancy: 6.7 % / Rmerge(I) obs: 0.101 / Rpim(I) all: 0.042 / Rrim(I) all: 0.109 / Χ2: 0.914 / Net I/σ(I): 7.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.2-2.246.41.05621180.7160.4511.1510.91999.9
2.24-2.286.81.00320700.760.4141.0870.93399.8
2.28-2.326.70.89521000.7660.3710.9710.90699.8
2.32-2.376.70.74520980.8260.310.8080.91499.9
2.37-2.426.80.63320980.8790.2610.6860.94999.9
2.42-2.486.70.54720990.9080.2260.5920.94499.7
2.48-2.546.80.46721130.9350.1930.5060.93799.9
2.54-2.616.70.37220710.9510.1540.4040.9199.8
2.61-2.696.70.31721140.9610.1320.3440.9399.7
2.69-2.776.30.24321010.9710.1040.2650.9299.5
2.77-2.8760.19620450.9740.0850.2140.93198.1
2.87-2.997.10.17421270.9840.070.1880.96599.9
2.99-3.127.10.1321120.9910.0520.140.932100
3.12-3.297.10.10821070.9920.0430.1160.9599.9
3.29-3.4970.08621050.9940.0350.0931.0299.6
3.49-3.766.90.07121310.9930.0290.0770.96999.6
3.76-4.146.10.06220720.9940.0270.0680.88698.2
4.14-4.7470.05721150.9960.0230.0610.85100
4.74-5.9770.05421430.9940.0220.0590.72599.8
5.97-506.50.05921630.9960.0250.0640.79299.1

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.8.0232refinement
PDB_EXTRACT3.24data extraction
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I9I

5i9i


Resolution: 2.19→46.39 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.92 / SU B: 6.213 / SU ML: 0.158 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.281 / ESU R Free: 0.216
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2401 1952 4.9 %RANDOM
Rwork0.1927 ---
obs0.1951 37721 92.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 122.8 Å2 / Biso mean: 31.109 Å2 / Biso min: 14.32 Å2
Baniso -1Baniso -2Baniso -3
1--0.34 Å2-0 Å20.11 Å2
2--0.19 Å2-0 Å2
3---0.02 Å2
Refinement stepCycle: final / Resolution: 2.19→46.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5768 0 37 59 5864
Biso mean--73.52 28.95 -
Num. residues----741
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0135950
X-RAY DIFFRACTIONr_bond_other_d0.0030.0175322
X-RAY DIFFRACTIONr_angle_refined_deg1.5651.6448080
X-RAY DIFFRACTIONr_angle_other_deg1.3871.58312297
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7935739
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.61322.376303
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.24815939
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4191532
X-RAY DIFFRACTIONr_chiral_restr0.0730.2782
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.026748
X-RAY DIFFRACTIONr_gen_planes_other0.0040.021315
LS refinement shellResolution: 2.2→2.242 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.29 84 -
Rwork0.26 1413 -
obs--47.05 %

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