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- PDB-5g3m: Discovery of a novel secreted phospholipase A2 (sPLA2) inhibitor. -

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Basic information

Entry
Database: PDB / ID: 5g3m
TitleDiscovery of a novel secreted phospholipase A2 (sPLA2) inhibitor.
ComponentsGROUP 10 SECRETORY PHOSPHOLIPASE A2
KeywordsHYDROLASE / SPLA2 / CARDIOVASCULAR DISEASE / INHIBITOR / FRAGMENT
Function / homology
Function and homology information


phosphatidylserine metabolic process / lysophospholipid transport / phosphatidylethanolamine metabolic process / phosphatidic acid metabolic process / production of molecular mediator involved in inflammatory response / platelet activating factor catabolic process / positive regulation of acrosome reaction / Acyl chain remodelling of PG / Acyl chain remodelling of PC / phospholipase activity ...phosphatidylserine metabolic process / lysophospholipid transport / phosphatidylethanolamine metabolic process / phosphatidic acid metabolic process / production of molecular mediator involved in inflammatory response / platelet activating factor catabolic process / positive regulation of acrosome reaction / Acyl chain remodelling of PG / Acyl chain remodelling of PC / phospholipase activity / Acyl chain remodelling of PI / intestinal stem cell homeostasis / Acyl chain remodelling of PS / Acyl chain remodelling of PE / 1-alkyl-2-acetylglycerophosphocholine esterase activity / Synthesis of PA / negative regulation of cholesterol efflux / arachidonate metabolic process / phosphatidylglycerol metabolic process / phosphatidylcholine catabolic process / phospholipase A2 activity / phosphatidylcholine metabolic process / positive regulation of macrophage derived foam cell differentiation / positive regulation of lipid storage / positive regulation of prostaglandin secretion / positive regulation of arachidonate secretion / macrophage activation / low-density lipoprotein particle remodeling / fertilization / phospholipase A2 / calcium-dependent phospholipase A2 activity / prostaglandin biosynthetic process / hair follicle morphogenesis / arachidonate secretion / regulation of macrophage activation / erythrocyte maturation / negative regulation of cytokine production involved in inflammatory response / phospholipid metabolic process / positive regulation of protein metabolic process / acrosomal vesicle / cholesterol homeostasis / cellular response to leukemia inhibitory factor / axon guidance / negative regulation of DNA-binding transcription factor activity / phospholipid binding / negative regulation of inflammatory response / defense response to virus / lysosome / calcium ion binding / extracellular space / extracellular region
Similarity search - Function
Phospholipase A2, aspartic acid active site / Phospholipase A2 aspartic acid active site. / Phospholipase A2 / Phospholipase A2, histidine active site / Phospholipase A2 histidine active site. / Phospholipase A2 / Phospholipase A2 domain / Phospholipase A2 / Phospholipase A2 / Phospholipase A2 domain ...Phospholipase A2, aspartic acid active site / Phospholipase A2 aspartic acid active site. / Phospholipase A2 / Phospholipase A2, histidine active site / Phospholipase A2 histidine active site. / Phospholipase A2 / Phospholipase A2 domain / Phospholipase A2 / Phospholipase A2 / Phospholipase A2 domain / Phospholipase A2 domain superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
4-BENZYLBENZAMIDE / DI(HYDROXYETHYL)ETHER / Group 10 secretory phospholipase A2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsSandmark, J. / Bodin, C. / Hallberg, K.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: Discovery of Azd2716: A Novel Secreted Phospholipase A2 (Spla2) Inhibitor for the Treatment of Coronary Artery Disease
Authors: Giordanetto, F. / Pettersen, D. / Starke, I. / Nordberg, P. / Dahlstrom, M. / Knerr, L. / Selmi, N. / Rosengren, B. / Larsson, L.O. / Sandmark, J. / Castaldo, M. / Dekker, N. / Karlsson, U. / Hurt-Camejo, E.
History
DepositionApr 29, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 14, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 9, 2016Group: Database references
Revision 1.2Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: GROUP 10 SECRETORY PHOSPHOLIPASE A2
B: GROUP 10 SECRETORY PHOSPHOLIPASE A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,74027
Polymers27,2892
Non-polymers2,45125
Water1,820101
1
A: GROUP 10 SECRETORY PHOSPHOLIPASE A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,02915
Polymers13,6451
Non-polymers1,38514
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: GROUP 10 SECRETORY PHOSPHOLIPASE A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,71112
Polymers13,6451
Non-polymers1,06611
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)27.570, 85.122, 103.316
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (-1, 0.001815, 0.007798), (0.007978, 0.3077, 0.9514), (-0.000673, 0.9515, -0.3077)
Vector: -6.257, -21.41, 29.1)

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein GROUP 10 SECRETORY PHOSPHOLIPASE A2 / SECRETED PHOSPHOLIPASE A2 / GROUP X SECRETORY PHOSPHOLIPASE A SPLA2-X / PHOSPHATIDYLCHOLINE 2-ACYLHYDROLASE 10


Mass: 13644.535 Da / Num. of mol.: 2 / Fragment: MATURE SPLA2-X, UNP RESIDUES 43-165
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET24A / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / Variant (production host): GOLD / References: UniProt: O15496, phospholipase A2

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Non-polymers , 5 types, 126 molecules

#2: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-9JH / 4-BENZYLBENZAMIDE


Mass: 211.259 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H13NO
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 101 / 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: 2.22 Å3/Da / Density % sol: 44.63 % / Description: NONE
Crystal growDetails: 40% PEG 400, 0.1 M BIS-TRIS PH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ / Wavelength: 1.5418
DetectorDate: Mar 9, 2007 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.84→103.3 Å / Num. obs: 21292 / % possible obs: 96 % / Observed criterion σ(I): 2 / Redundancy: 5 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 12
Reflection shellResolution: 1.84→1.94 Å / Redundancy: 4 % / Rmerge(I) obs: 0.66 / Mean I/σ(I) obs: 2.5 / % possible all: 77

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→65.7 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.909 / SU B: 3.51 / SU ML: 0.104 / Cross valid method: THROUGHOUT / ESU R: 0.169 / ESU R Free: 0.148 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.23222 1060 5.1 %RANDOM
Rwork0.1985 ---
obs0.20032 19648 95.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.746 Å2
Baniso -1Baniso -2Baniso -3
1--0.19 Å20 Å20 Å2
2--1.27 Å20 Å2
3----1.08 Å2
Refinement stepCycle: LAST / Resolution: 1.85→65.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1888 0 151 101 2140
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192124
X-RAY DIFFRACTIONr_bond_other_d0.0070.021929
X-RAY DIFFRACTIONr_angle_refined_deg1.272.0122849
X-RAY DIFFRACTIONr_angle_other_deg0.79334476
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.8535256
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.8542592
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.39815317
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.862158
X-RAY DIFFRACTIONr_chiral_restr0.0750.2287
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0212336
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02446
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_it0.9651.833994
X-RAY DIFFRACTIONr_mcbond_other0.9661.83993
X-RAY DIFFRACTIONr_mcangle_it1.5832.7391242
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.4482.1621130
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
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: 1.845→1.893 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.748 22 -
Rwork0.631 548 -
obs--37.13 %

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