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- PDB-7laf: 15-lipoxygenase-2 loop mutant bound to imidazole-based inhibitor -

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Basic information

Entry
Database: PDB / ID: 7laf
Title15-lipoxygenase-2 loop mutant bound to imidazole-based inhibitor
ComponentsPolyunsaturated fatty acid lipoxygenase ALOX15B
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / Lipoxygenase / inhibitor / allostery / complex / OXIDOREDUCTASE / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex / LIPID BINDING PROTEIN
Function / homology
Function and homology information


endocannabinoid signaling pathway / arachidonate 8(S)-lipoxygenase activity / lipoxin A4 biosynthetic process / cannabinoid biosynthetic process / linoleate 9S-lipoxygenase activity / arachidonate 15-lipoxygenase / arachidonate 15-lipoxygenase activity / Synthesis of 15-eicosatetraenoic acid derivatives / linoleate 13S-lipoxygenase activity / Oxidoreductases; Acting on single donors with incorporation of molecular oxygen (oxygenases); With incorporation of two atoms of oxygen ...endocannabinoid signaling pathway / arachidonate 8(S)-lipoxygenase activity / lipoxin A4 biosynthetic process / cannabinoid biosynthetic process / linoleate 9S-lipoxygenase activity / arachidonate 15-lipoxygenase / arachidonate 15-lipoxygenase activity / Synthesis of 15-eicosatetraenoic acid derivatives / linoleate 13S-lipoxygenase activity / Oxidoreductases; Acting on single donors with incorporation of molecular oxygen (oxygenases); With incorporation of two atoms of oxygen / regulation of epithelial cell differentiation / lipoxygenase pathway / positive regulation of peroxisome proliferator activated receptor signaling pathway / arachidonic acid metabolic process / lipid oxidation / prostate gland development / negative regulation of growth / positive regulation of macrophage derived foam cell differentiation / hepoxilin biosynthetic process / linoleic acid metabolic process / positive regulation of keratinocyte differentiation / negative regulation of cell cycle / phospholipid metabolic process / positive regulation of chemokine production / negative regulation of cell migration / adherens junction / lipid metabolic process / cytoskeleton / iron ion binding / negative regulation of cell population proliferation / focal adhesion / lipid binding / apoptotic process / calcium ion binding / extracellular exosome / membrane / nucleus / plasma membrane / cytosol
Similarity search - Function
Lipoxygenase, vertebrates, PLAT domain / Lipoxygenase, mammalian / Lipoxygenase, conserved site / Lipoxygenases iron-binding region signature 2. / Lipoxygenase, iron binding site / Lipoxygenases iron-binding region signature 1. / Lipoxygenase / Lipoxygenase, C-terminal / Lipoxigenase, C-terminal domain superfamily / Lipoxygenase ...Lipoxygenase, vertebrates, PLAT domain / Lipoxygenase, mammalian / Lipoxygenase, conserved site / Lipoxygenases iron-binding region signature 2. / Lipoxygenase, iron binding site / Lipoxygenases iron-binding region signature 1. / Lipoxygenase / Lipoxygenase, C-terminal / Lipoxigenase, C-terminal domain superfamily / Lipoxygenase / Lipoxygenase iron-binding catalytic domain profile. / Lipoxygenase homology 2 (beta barrel) domain / PLAT/LH2 domain / PLAT/LH2 domain superfamily / PLAT/LH2 domain / PLAT domain profile.
Similarity search - Domain/homology
: / Chem-XRP / Polyunsaturated fatty acid lipoxygenase ALOX15B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.44 Å
AuthorsNewcomer, M.E. / Gilbert, N.C. / Neau, D.B.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P30 GM124165 United States
CitationJournal: Bioorg.Med.Chem. / Year: 2021
Title: Kinetic and structural investigations of novel inhibitors of human epithelial 15-lipoxygenase-2.
Authors: Tsai, W.C. / Gilbert, N.C. / Ohler, A. / Armstrong, M. / Perry, S. / Kalyanaraman, C. / Yasgar, A. / Rai, G. / Simeonov, A. / Jadhav, A. / Standley, M. / Lee, H.W. / Crews, P. / Iavarone, A. ...Authors: Tsai, W.C. / Gilbert, N.C. / Ohler, A. / Armstrong, M. / Perry, S. / Kalyanaraman, C. / Yasgar, A. / Rai, G. / Simeonov, A. / Jadhav, A. / Standley, M. / Lee, H.W. / Crews, P. / Iavarone, A.T. / Jacobson, M.P. / Neau, D.B. / Offenbacher, A.R. / Newcomer, M. / Holman, T.R.
History
DepositionJan 6, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 19, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Polyunsaturated fatty acid lipoxygenase ALOX15B
B: Polyunsaturated fatty acid lipoxygenase ALOX15B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)155,4226
Polymers154,7502
Non-polymers6734
Water6,575365
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, protein is a mixture of monomer and dimer from gel filtration column.
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1620 Å2
ΔGint-12 kcal/mol
Surface area50370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)189.277, 43.313, 185.070
Angle α, β, γ (deg.)90.000, 118.203, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

#1: Protein Polyunsaturated fatty acid lipoxygenase ALOX15B / 15-lipoxygenase 2 / 15-LOX-2 / Arachidonate 15-lipoxygenase B / 15-LOX-B / Arachidonate 15- ...15-lipoxygenase 2 / 15-LOX-2 / Arachidonate 15-lipoxygenase B / 15-LOX-B / Arachidonate 15-lipoxygenase type II / Linoleate 13-lipoxygenase 15-LOb


Mass: 77374.922 Da / Num. of mol.: 2 / Mutation: delete PPVLPLL
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ALOX15B / Production host: Escherichia coli (E. coli) / References: UniProt: O15296, arachidonate 15-lipoxygenase
#2: Chemical ChemComp-MN / MANGANESE (II) ION


Mass: 54.938 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mn
#3: Chemical ChemComp-XRP / 3-{[(4-methylphenyl)methyl]sulfanyl}-1-phenyl-1H-1,2,4-triazole


Mass: 281.375 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H15N3S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 365 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.16 Å3/Da / Density % sol: 43.06 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7 / Details: 20% DMSO, 20% Jeffamine M-2070

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97918 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 12, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97918 Å / Relative weight: 1
ReflectionResolution: 2.44→163.1 Å / Num. obs: 49895 / % possible obs: 99.32 % / Redundancy: 2 % / Biso Wilson estimate: 33.26 Å2 / CC1/2: 0.976 / Net I/σ(I): 7.32
Reflection shellResolution: 2.44→2.527 Å / Redundancy: 2 % / Mean I/σ(I) obs: 1.18 / Num. unique obs: 4917 / CC1/2: 0.369 / CC star: 0.734 / % possible all: 99.78

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Processing

Software
NameVersionClassification
PHENIXdev_3908refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4nre

4nre


Resolution: 2.44→163.1 Å / SU ML: 0.3498 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.9574
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2722 2001 4.01 %
Rwork0.2338 47877 -
obs0.2354 49878 99.32 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.27 Å2
Refinement stepCycle: LAST / Resolution: 2.44→163.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10467 0 42 365 10874
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00810804
X-RAY DIFFRACTIONf_angle_d1.047414716
X-RAY DIFFRACTIONf_chiral_restr0.06431600
X-RAY DIFFRACTIONf_plane_restr0.00471911
X-RAY DIFFRACTIONf_dihedral_angle_d17.31793944
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.44-2.50.34421510.32743363X-RAY DIFFRACTION99.86
2.5-2.570.35361320.31733438X-RAY DIFFRACTION99.58
2.57-2.640.35461310.30473343X-RAY DIFFRACTION99.6
2.64-2.730.32891550.30073413X-RAY DIFFRACTION99.44
2.73-2.830.29681370.28453360X-RAY DIFFRACTION99.6
2.83-2.940.33921430.28473458X-RAY DIFFRACTION99.89
2.94-3.070.34651420.28543379X-RAY DIFFRACTION99.75
3.07-3.240.29581450.24813412X-RAY DIFFRACTION99.78
3.24-3.440.26651370.23513417X-RAY DIFFRACTION99.41
3.44-3.70.23121430.21553430X-RAY DIFFRACTION99.22
3.7-4.080.24621430.19593395X-RAY DIFFRACTION98.63
4.08-4.670.21851400.18443423X-RAY DIFFRACTION98.62
4.67-5.880.24821480.20143453X-RAY DIFFRACTION98.85
5.88-163.10.23981540.19983593X-RAY DIFFRACTION98.4

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