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- PDB-5ow8: Indole-2 carboxamides as selective secreted phospholipase A2 type... -

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Basic information

Entry
Database: PDB / ID: 5ow8
TitleIndole-2 carboxamides as selective secreted phospholipase A2 type X (sPLA2-X) inhibitors
ComponentsGroup 10 secretory phospholipase A2
KeywordsLIPID BINDING PROTEIN / Inhibitor / secreted / phospholipase
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 / intestinal stem cell homeostasis / 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 / intestinal stem cell homeostasis / phospholipase activity / Acyl chain remodelling of PC / Acyl chain remodelling of PI / Acyl chain remodelling of PS / Acyl chain remodelling of PE / 1-alkyl-2-acetylglycerophosphocholine esterase activity / Synthesis of PA / negative regulation of cholesterol efflux / arachidonic acid metabolic process / phosphatidylglycerol metabolic process / calcium-dependent phospholipase A2 activity / phosphatidylcholine catabolic process / positive regulation of prostaglandin secretion / positive regulation of macrophage derived foam cell differentiation / phosphatidylcholine metabolic process / positive regulation of lipid storage / macrophage activation / positive regulation of arachidonic acid secretion / low-density lipoprotein particle remodeling / fertilization / phospholipase A2 / phospholipase A2 activity / prostaglandin biosynthetic process / regulation of macrophage activation / arachidonic acid secretion / hair follicle morphogenesis / erythrocyte maturation / negative regulation of cytokine production involved in inflammatory response / phospholipid metabolic process / positive regulation of protein metabolic process / cellular response to leukemia inhibitory factor / acrosomal vesicle / cholesterol homeostasis / axon guidance / phospholipid binding / negative regulation of DNA-binding transcription factor activity / 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
1-[3-(trifluoromethyl)phenyl]indole-2-carboxamide / DI(HYDROXYETHYL)ETHER / Group 10 secretory phospholipase A2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsSandmark, J.S. / Roth, R.G. / Knerr, L. / Bodin, C. / Pettersen, D.
CitationJournal: Acs Med.Chem.Lett. / Year: 2018
Title: Discovery of a Series of Indole-2 Carboxamides as Selective Secreted Phospholipase A2Type X (sPLA2-X) Inhibitors.
Authors: Knerr, L. / Giordanetto, F. / Nordberg, P. / Pettersen, D. / Selmi, N. / Beisel, H.G. / de la Motte, H. / Olsson, T. / Perkins, T.D.J. / Herslof, M. / Mansson, A. / Dahlstrom, M. / Starke, I. ...Authors: Knerr, L. / Giordanetto, F. / Nordberg, P. / Pettersen, D. / Selmi, N. / Beisel, H.G. / de la Motte, H. / Olsson, T. / Perkins, T.D.J. / Herslof, M. / Mansson, A. / Dahlstrom, M. / Starke, I. / Broddefalk, J. / Saarinen, G. / Klingegard, F. / Hurt-Camejo, E. / Rosengren, B. / Brengdahl, J. / Jansen, F. / Rohman, M. / Sandmark, J. / Hallberg, K. / Akerud, T. / Roth, R.G. / Ahlqvist, M.
History
DepositionAug 31, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 1, 2018Provider: repository / Type: Initial release
Revision 1.1May 5, 2021Group: Database references / Derived calculations
Category: citation / pdbx_struct_assembly ...citation / pdbx_struct_assembly / pdbx_struct_assembly_gen / pdbx_struct_assembly_prop / pdbx_struct_conn_angle / pdbx_struct_oper_list / struct_conn
Item: _citation.journal_abbrev / _pdbx_struct_assembly_gen.assembly_id ..._citation.journal_abbrev / _pdbx_struct_assembly_gen.assembly_id / _pdbx_struct_assembly_gen.oper_expression / _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_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _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_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _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_asym_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

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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)29,27523
Polymers27,2892
Non-polymers1,98621
Water1,928107
1
A: Group 10 secretory phospholipase A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,79713
Polymers13,6451
Non-polymers1,15212
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Group 10 secretory phospholipase A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,47810
Polymers13,6451
Non-polymers8349
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)27.652, 85.367, 102.954
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Group 10 secretory phospholipase A2 / Group X secretory phospholipase A2 / sPLA2-X / Phosphatidylcholine 2-acylhydrolase 10


Mass: 13644.535 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLA2G10 / Plasmid: pET24 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Gold / References: UniProt: O15496, phospholipase A2

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Non-polymers , 6 types, 128 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 / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-AYN / 1-[3-(trifluoromethyl)phenyl]indole-2-carboxamide


Mass: 304.267 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H11F3N2O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C4H10O3
#6: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 107 / 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: 2.23 Å3/Da / Density % sol: 44.75 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 37-45% PEG400 0.1M bis-Tris pH 5.6-5.9 / PH range: 5.6-5.9

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ DW / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN A200 / Detector: CCD / Date: Mar 9, 2007
RadiationMonochromator: Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→44.083 Å / Num. obs: 19430 / % possible obs: 97.1 % / Redundancy: 5.5 % / Rpim(I) all: 0.069 / Rrim(I) all: 0.166 / Rsym value: 0.15 / Net I/av σ(I): 4.2 / Net I/σ(I): 7.1
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.9-1.953.81.0570.711010.591.221.05777.9
1.95-24.30.870.912380.4510.9870.8790.5
2-2.065.30.742113550.3420.820.74299.8
2.06-2.125.80.6151.213300.2720.6750.61596.5
2.12-2.195.80.4891.612680.2170.5360.48999.6
2.19-2.275.70.3861.912600.1730.4240.38699.8
2.27-2.365.80.3482.211840.1550.3820.34897.8
2.36-2.455.80.2882.611820.1290.3170.288100
2.45-2.565.80.2582.911130.1150.2840.25898.7
2.56-2.695.80.2163.510830.0970.2370.216100
2.69-2.835.80.1834.110360.0820.2010.18399.4
2.83-35.70.1544.79820.070.170.154100
3-3.215.80.1275.59250.0580.140.12799.8
3.21-3.475.70.1046.38760.0480.1150.10499.9
3.47-3.85.80.0917.17940.0410.10.091100
3.8-4.255.70.087.47410.0370.0890.08100
4.25-4.915.60.0727.86570.0330.0790.072100
4.91-6.015.60.0659.55720.0290.0720.065100
6.01-8.55.40.0758.14580.0350.0830.075100
8.5-44.0834.80.0617.52750.0310.0690.06197.2

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Processing

Software
NameVersionClassification
SCALA3.3.21data scaling
REFMAC5.8.0135refinement
PDB_EXTRACT3.22data extraction
iMOSFLMdata reduction
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.9→44 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.898 / SU B: 4.589 / SU ML: 0.13 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.216 / ESU R Free: 0.179
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2523 950 5.3 %RANDOM
Rwork0.2157 ---
obs0.2176 17095 89.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 55.74 Å2 / Biso mean: 23.132 Å2 / Biso min: 13.51 Å2
Baniso -1Baniso -2Baniso -3
1--0.03 Å2-0 Å20 Å2
2--0.12 Å20 Å2
3----0.08 Å2
Refinement stepCycle: final / Resolution: 1.9→44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1888 0 117 107 2112
Biso mean--31.3 31.18 -
Num. residues----246
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192078
X-RAY DIFFRACTIONr_bond_other_d0.0060.021849
X-RAY DIFFRACTIONr_angle_refined_deg1.2132.0032814
X-RAY DIFFRACTIONr_angle_other_deg0.93734289
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.2025252
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.17324.88990
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.49115314
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.751158
X-RAY DIFFRACTIONr_chiral_restr0.070.2284
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212320
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02442
LS refinement shellResolution: 1.9→1.949 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.319 50 -
Rwork0.339 834 -
all-884 -
obs--60.1 %

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