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- PDB-5ye9: The crystal structure of Lp-PLA2 in complex with a novel inhibitor -

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Basic information

Entry
Database: PDB / ID: 5ye9
TitleThe crystal structure of Lp-PLA2 in complex with a novel inhibitor
ComponentsPlatelet-activating factor acetylhydrolase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / hydrolase inhibitor / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
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-8U6 / Platelet-activating factor acetylhydrolase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.876 Å
AuthorsLiu, Q.F. / Xu, Y.C.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2.
Authors: Liu, Q. / Huang, F. / Yuan, X. / Wang, K. / Zou, Y. / Shen, J. / Xu, Y.
History
DepositionSep 15, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 25, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 22, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)89,0157
Polymers87,8122
Non-polymers1,2035
Water4,017223
1
A: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,6525
Polymers43,9061
Non-polymers7464
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area190 Å2
ΔGint-15 kcal/mol
Surface area14130 Å2
MethodPISA
2
B: Platelet-activating factor acetylhydrolase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)44,3632
Polymers43,9061
Non-polymers4581
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area14050 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.091, 83.612, 96.601
Angle α, β, γ (deg.)90.000, 114.900, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein Platelet-activating factor acetylhydrolase / Lp-PLA2 / PAF acetylhydrolase / 1-alkyl-2-acetylglycerophosphocholine esterase / 2-acetyl-1- ...Lp-PLA2 / 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: 43905.816 Da / Num. of mol.: 2 / Fragment: UNP residues 47-429
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLA2G7, PAFAH / Production host: Escherichia coli (E. coli)
References: UniProt: Q13093, 1-alkyl-2-acetylglycerophosphocholine esterase
#2: Chemical ChemComp-8U6 / N-[4-[(3-cyano-4-naphthalen-2-yloxy-phenyl)sulfamoyl]phenyl]ethanamide


Mass: 457.501 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H19N3O4S
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 223 / 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: 2.4 Å3/Da / Density % sol: 48.76 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.1M MOPS pH 6.6, 0.4M Li2SO4, 27% (w/v) (NH4)2SO4, 1M Na-Ac, 1.4% 1,4-butanediol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.9791 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 9, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 1.876→87.62 Å / Num. obs: 66597 / % possible obs: 97.9 % / Redundancy: 7.3 % / Biso Wilson estimate: 22.74 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.154 / Rpim(I) all: 0.061 / Rrim(I) all: 0.166 / Net I/σ(I): 10.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.88-1.987.51.10599240.7180.4321.187100
5.93-87.626.90.05621980.9960.0230.06198.6

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation4.76 Å87.62 Å
Translation4.76 Å87.62 Å

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Processing

Software
NameVersionClassification
Aimless0.5.29data scaling
PHENIX(phenix.refine: 1.9_1692)refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5I8P

5i8p


Resolution: 1.876→29.736 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.05
RfactorNum. reflection% reflection
Rfree0.2008 3333 5.01 %
Rwork0.1669 --
obs0.1686 66566 97.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 87.06 Å2 / Biso mean: 25.7158 Å2 / Biso min: 10.04 Å2
Refinement stepCycle: final / Resolution: 1.876→29.736 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5713 0 81 223 6017
Biso mean--38.05 29.81 -
Num. residues----740
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0075938
X-RAY DIFFRACTIONf_angle_d1.0718063
X-RAY DIFFRACTIONf_chiral_restr0.047874
X-RAY DIFFRACTIONf_plane_restr0.0051034
X-RAY DIFFRACTIONf_dihedral_angle_d12.512197
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 24

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.8756-1.90240.30961630.250926582821100
1.9024-1.93080.2611630.226126552818100
1.9308-1.9610.251350.207526602795100
1.961-1.99310.23841410.19627052846100
1.9931-2.02750.22121410.188726962837100
2.0275-2.06430.24271070.19262105221280
2.0643-2.1040.19951420.181727162858100
2.104-2.14690.20311400.175526822822100
2.1469-2.19360.1961440.169426832827100
2.1936-2.24460.23961220.17882266238885
2.2446-2.30070.19311380.174326822820100
2.3007-2.36290.24061400.173926682808100
2.3629-2.43240.21921470.168526502797100
2.4324-2.51090.21611530.172926912844100
2.5109-2.60060.22431280.171427292857100
2.6006-2.70460.21441460.172226572803100
2.7046-2.82760.2121340.177327092843100
2.8276-2.97660.23651380.173327002838100
2.9766-3.16290.23071360.174826752811100
3.1629-3.40680.19651500.16427002850100
3.4068-3.7490.18081360.14982467260391
3.749-4.29010.15411290.14162590271995
4.2901-5.39980.14361280.138527312859100
5.3998-29.74010.18751320.16332758289099
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.0797-0.03340.39191.0851-0.31912.93160.02880.0987-0.1113-0.2269-0.0883-0.05960.31960.07180.07020.22120.0260.02520.1307-0.02320.1905-35.9982-40.909715.6206
24.1793-0.3562-1.26771.8233-0.39112.2048-0.04890.1905-0.1603-0.1112-0.06060.43660.2931-0.35910.15410.1582-0.0257-0.0190.15790.00250.1609-48.8331-38.227520.7059
31.2490.17420.02251.9755-0.36741.61920.00490.0146-0.0808-0.0597-0.01670.10590.1804-0.17190.030.1502-0.0085-0.01190.1412-0.0140.1791-41.3943-37.524420.2646
43.5697-3.5161-1.44017.7872.89553.2503-0.1302-0.13640.00080.22340.1102-0.21710.06630.06370.03470.1467-0.00790.00650.17660.03960.1533-30.6823-28.206626.8597
51.30230.0999-0.1331.9656-0.15791.1224-0.0529-0.0254-0.1271-0.0521-0.0478-0.29850.16180.1440.05840.14760.03620.02470.14450.01570.1617-29.5061-28.028416.7582
61.18830.3292-0.17532.8954-0.25481.970.01180.07820.0965-0.1482-0.01940.1587-0.0579-0.16510.02750.17070.0648-0.01450.17770.01840.1842-42.0784-18.438410.8022
71.7318-0.87470.02792.48150.04561.21370.09470.33110.0467-0.5393-0.1531-0.09530.0124-0.0370.04580.2750.05290.040.27320.00560.1845-34.0153-21.45971.215
81.17430.048-0.09591.3667-0.25221.674-0.0224-0.13010.07330.10030.0209-0.0715-0.01240.15770.00850.13380.0003-0.01450.1506-0.02130.12363.6688-26.959732.8792
91.8876-0.3711-0.25661.94910.42261.5937-0.00020.0192-0.06130.0551-0.05750.18660.0193-0.09730.04590.1213-0.0049-0.00110.14520.00120.1231-6.46-33.456923.192
100.6962-0.0934-0.20811.47640.37141.16970.0114-0.0171-0.05020.02870.0484-0.09890.01840.1305-0.04610.16330.0190.00530.18110.00710.149211.1594-37.42514.6264
113.577-1.55770.04272.1662-0.66942.3278-0.0280.23620.1699-0.229-0.0143-0.0284-0.1770.09190.06310.1908-0.02850.01390.15670.02960.14727.4477-26.79217.9583
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 55 through 86 )A55 - 86
2X-RAY DIFFRACTION2chain 'A' and (resid 87 through 111 )A87 - 111
3X-RAY DIFFRACTION3chain 'A' and (resid 112 through 210 )A112 - 210
4X-RAY DIFFRACTION4chain 'A' and (resid 211 through 240 )A211 - 240
5X-RAY DIFFRACTION5chain 'A' and (resid 241 through 324 )A241 - 324
6X-RAY DIFFRACTION6chain 'A' and (resid 325 through 376 )A325 - 376
7X-RAY DIFFRACTION7chain 'A' and (resid 377 through 425 )A377 - 425
8X-RAY DIFFRACTION8chain 'B' and (resid 55 through 210 )B55 - 210
9X-RAY DIFFRACTION9chain 'B' and (resid 211 through 312 )B211 - 312
10X-RAY DIFFRACTION10chain 'B' and (resid 313 through 376 )B313 - 376
11X-RAY DIFFRACTION11chain 'B' and (resid 377 through 424 )B377 - 425

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