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- PDB-6m07: Crystal structure of Lp-PLA2 in complex with a novel covalent inh... -

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Basic information

Entry
Database: PDB / ID: 6m07
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-BWO / Platelet-activating factor acetylhydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.64 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: Derived calculations / Non-polymer description / Structure summary
Category: chem_comp / entity / pdbx_entity_nonpoly
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 2.2Oct 30, 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)85,3674
Polymers84,1042
Non-polymers1,2632
Water1448
1
A: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6832
Polymers42,0521
Non-polymers6321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,6832
Polymers42,0521
Non-polymers6321
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)112.687, 77.857, 94.698
Angle α, β, γ (deg.)90.000, 115.320, 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: 42051.859 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-BWO / (2S)-2-[(E)-3-[2-(diethylamino)ethyl-[[4-[4-(trifluoromethyl)-2-[2,2,2-tris(fluoranyl)ethoxy]phenyl]phenyl]methyl]amino]-1-oxidanyl-3-oxidanylidene-prop-1-enyl]pyrrolidine-1-carboxylic acid


Mass: 631.606 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H35F6N3O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 8 / 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: 2.23 Å3/Da / Density % sol: 44.9 %
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: BL18U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.64→50 Å / Num. obs: 21641 / % possible obs: 99.8 % / Redundancy: 6.2 % / Rmerge(I) obs: 0.2 / Rpim(I) all: 0.086 / Rrim(I) all: 0.218 / Χ2: 0.98 / Net I/σ(I): 4.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
2.65-2.74.21.30610480.5590.6721.4750.86199.4
2.7-2.744.41.29710730.540.651.4580.86798.9
2.74-2.84.71.17210640.5350.5811.3140.84399.6
2.8-2.855.21.04510910.6840.491.1580.85299.1
2.85-2.925.81.06510360.7790.4741.1680.87699.9
2.92-2.986.20.9311130.8290.4021.0150.915100
2.98-3.066.50.7910580.8440.3330.8590.92199.9
3.06-3.146.50.710840.9320.2940.760.929100
3.14-3.236.70.66110700.920.2740.7170.995100
3.23-3.346.70.52310760.9250.2190.5681.059100
3.34-3.466.70.41610860.9580.1750.4511.081100
3.46-3.66.20.33610920.9470.1460.3671.178100
3.6-3.766.40.28710740.9670.1240.3131.156100
3.76-3.9670.23710950.9780.0970.2561.114100
3.96-4.2170.19310690.9820.0780.2081.22100
4.21-4.536.90.1611060.9840.0660.1731.141100
4.53-4.996.70.13610880.9890.0560.1470.971100
4.99-5.716.20.12710910.9870.0560.1390.896100
5.71-7.1970.12410970.9910.050.1340.90999.7
7.19-506.30.07511300.9920.0330.0820.593100

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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: 2.64→44.95 Å / Cor.coef. Fo:Fc: 0.915 / Cor.coef. Fo:Fc free: 0.877 / SU B: 14.103 / SU ML: 0.294 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.394
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.249 934 4.9 %RANDOM
Rwork0.2001 ---
obs0.2026 18126 87.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 151.55 Å2 / Biso mean: 38.382 Å2 / Biso min: 11.04 Å2
Baniso -1Baniso -2Baniso -3
1--0.46 Å20 Å20.51 Å2
2---0.82 Å2-0 Å2
3---0.55 Å2
Refinement stepCycle: final / Resolution: 2.64→44.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5655 0 86 8 5749
Biso mean--76.54 23.86 -
Num. residues----738
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0135891
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175159
X-RAY DIFFRACTIONr_angle_refined_deg1.6891.6568017
X-RAY DIFFRACTIONr_angle_other_deg1.291.59111888
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.0485736
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.90722.013298
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.65315875
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.2471534
X-RAY DIFFRACTIONr_chiral_restr0.0670.2780
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.026744
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021324
LS refinement shellResolution: 2.645→2.713 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.387 28 -
Rwork0.222 501 -
all-529 -
obs--33.48 %

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