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- PDB-3e6n: Structure of murine INOS oxygenase domain with inhibitor AR-C125813 -

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Basic information

Entry
Database: PDB / ID: 3e6n
TitleStructure of murine INOS oxygenase domain with inhibitor AR-C125813
ComponentsNitric oxide synthase, inducible
KeywordsOXIDOREDUCTASE / NITRIC OXIDe / NOS / HEME / tetrahydrobiopterin / Calmodulin-binding / FAD / FMN / Iron / Metal-binding / NADP / Polymorphism / Zinc
Function / homology
Function and homology information


Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / peptidyl-cysteine S-nitrosylation / Peroxisomal protein import / prostaglandin secretion / tetrahydrobiopterin binding / arginine binding / superoxide metabolic process / regulation of cytokine production involved in inflammatory response / cortical cytoskeleton ...Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / peptidyl-cysteine S-nitrosylation / Peroxisomal protein import / prostaglandin secretion / tetrahydrobiopterin binding / arginine binding / superoxide metabolic process / regulation of cytokine production involved in inflammatory response / cortical cytoskeleton / cellular response to cytokine stimulus / Fc-gamma receptor signaling pathway involved in phagocytosis / nitric-oxide synthase (NADPH) / nitric-oxide synthase activity / L-arginine catabolic process / nitric oxide biosynthetic process / regulation of insulin secretion / positive regulation of interleukin-8 production / response to bacterium / circadian rhythm / negative regulation of protein catabolic process / cellular response to type II interferon / positive regulation of interleukin-6 production / cellular response to xenobiotic stimulus / peroxisome / FMN binding / NADP binding / flavin adenine dinucleotide binding / regulation of cell population proliferation / cellular response to lipopolysaccharide / response to lipopolysaccharide / calmodulin binding / response to hypoxia / defense response to bacterium / inflammatory response / negative regulation of gene expression / heme binding / perinuclear region of cytoplasm / protein homodimerization activity / metal ion binding / cytoplasm / cytosol
Similarity search - Function
Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / Nitric-oxide synthase, eukaryote / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain superfamily / Nitric oxide synthase, domain 2 superfamily ...Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / Nitric-oxide synthase, eukaryote / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain superfamily / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / : / Nitric oxide synthase, oxygenase domain / Nitric oxide synthase (NOS) signature. / Sulfite reductase [NADPH] flavoprotein alpha-component-like, FAD-binding / NADPH-cytochrome p450 reductase, FAD-binding, alpha-helical domain superfamily / FAD binding domain / Flavodoxin-like / Flavoprotein pyridine nucleotide cytochrome reductase / Flavodoxin / Flavodoxin-like domain profile. / Flavodoxin/nitric oxide synthase / Oxidoreductase FAD/NAD(P)-binding / Oxidoreductase NAD-binding domain / FAD-binding domain, ferredoxin reductase-type / Ferredoxin-NADP reductase (FNR), nucleotide-binding domain / Ferredoxin reductase-type FAD binding domain profile. / Riboflavin synthase-like beta-barrel / Flavoprotein-like superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
4-METHYL-6-PROPYLPYRIDIN-2-AMINE / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase, inducible
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsGarcin, E.D. / Arvai, A.S. / Rosenfeld, R.J. / Kroeger, M.D. / Crane, B.R. / Andersson, G. / Andrews, G. / Hamley, P.J. / Mallinder, P.R. / Nicholls, D.J. ...Garcin, E.D. / Arvai, A.S. / Rosenfeld, R.J. / Kroeger, M.D. / Crane, B.R. / Andersson, G. / Andrews, G. / Hamley, P.J. / Mallinder, P.R. / Nicholls, D.J. / St-Gallay, S.A. / Tinker, A.C. / Gensmantel, N.P. / Mete, A. / Cheshire, D.R. / Connolly, S. / Stueh, D.J. / Aberg, A. / Wallace, A.V. / Tainer, J.A. / Getzoff, E.D.
CitationJournal: Nat.Chem.Biol. / Year: 2008
Title: Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.
Authors: Garcin, E.D. / Arvai, A.S. / Rosenfeld, R.J. / Kroeger, M.D. / Crane, B.R. / Andersson, G. / Andrews, G. / Hamley, P.J. / Mallinder, P.R. / Nicholls, D.J. / St-Gallay, S.A. / Tinker, A.C. / ...Authors: Garcin, E.D. / Arvai, A.S. / Rosenfeld, R.J. / Kroeger, M.D. / Crane, B.R. / Andersson, G. / Andrews, G. / Hamley, P.J. / Mallinder, P.R. / Nicholls, D.J. / St-Gallay, S.A. / Tinker, A.C. / Gensmantel, N.P. / Mete, A. / Cheshire, D.R. / Connolly, S. / Stuehr, D.J. / Aberg, A. / Wallace, A.V. / Tainer, J.A. / Getzoff, E.D.
History
DepositionAug 15, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 7, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 25, 2017Group: Refinement description / Category: software
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Nitric oxide synthase, inducible
B: Nitric oxide synthase, inducible
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,2588
Polymers100,2422
Non-polymers2,0166
Water8,881493
1
A: Nitric oxide synthase, inducible
hetero molecules

A: Nitric oxide synthase, inducible
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,2588
Polymers100,2422
Non-polymers2,0166
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation10_554-y,-x,-z-1/61
Buried area4530 Å2
ΔGint-26 kcal/mol
Surface area35300 Å2
MethodPISA
2
B: Nitric oxide synthase, inducible
hetero molecules

B: Nitric oxide synthase, inducible
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,2588
Polymers100,2422
Non-polymers2,0166
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_554x-y,-y,-z-11
Buried area4530 Å2
ΔGint-29 kcal/mol
Surface area35340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)213.963, 213.963, 112.082
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-1000-

HOH

21A-1141-

HOH

31A-1149-

HOH

41B-950-

HOH

51B-1027-

HOH

61B-1084-

HOH

71B-1143-

HOH

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Components

#1: Protein Nitric oxide synthase, inducible / Inducible NO synthase / Inducible NOS / iNOS / NOS type II / Macrophage NOS / MAC-NOS


Mass: 50120.953 Da / Num. of mol.: 2 / Fragment: UNP residues 66-498
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Nos2, Inosl / Production host: Escherichia coli (E. coli) / References: UniProt: P29477, nitric-oxide synthase (NADPH)
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN


Mass: 241.247 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H15N5O3
#4: Chemical ChemComp-AS3 / 4-METHYL-6-PROPYLPYRIDIN-2-AMINE


Mass: 150.221 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H14N2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 493 / 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: 3.69 Å3/Da / Density % sol: 66.69 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6
Details: LITHIUM SULFATE, MES, BOG, pH 6.0, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-1 / Wavelength: 0.98 Å
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Dec 9, 1998
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.4→20 Å / Num. obs: 57844 / % possible obs: 97.7 % / Observed criterion σ(I): 0 / Redundancy: 6.9 % / Rmerge(I) obs: 0.05
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 6.6 % / Rmerge(I) obs: 0.36 / % possible all: 94.7

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Processing

Software
NameVersionClassificationNB
CNS1.1refinement
PDB_EXTRACT3.006data extraction
MAR345data collection
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→19.99 Å / Rfactor Rfree error: 0.005 / Occupancy max: 1 / Occupancy min: 0.5 / Data cutoff high absF: 406306 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: ENGH & HUBER
RfactorNum. reflection% reflectionSelection details
Rfree0.27 2613 5.1 %RANDOM
Rwork0.233 ---
obs-51440 87 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 41.27 Å2 / ksol: 0.33 e/Å3
Displacement parametersBiso max: 110.15 Å2 / Biso mean: 48.982 Å2 / Biso min: 19.96 Å2
Baniso -1Baniso -2Baniso -3
1--12.02 Å2-3.02 Å20 Å2
2---12.02 Å20 Å2
3---24.04 Å2
Refinement stepCycle: LAST / Resolution: 2.4→19.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6726 0 142 493 7361
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d23.2
X-RAY DIFFRACTIONc_improper_angle_d1.21
X-RAY DIFFRACTIONc_mcbond_it1.39
X-RAY DIFFRACTIONc_mcangle_it2.34
X-RAY DIFFRACTIONc_scbond_it1.92
X-RAY DIFFRACTIONc_scangle_it2.88
LS refinement shellResolution: 2.4→2.55 Å / Rfactor Rfree error: 0.021 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.393 357 5 %
Rwork0.345 6757 -
all-7114 -
obs--73.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1TOPHCSDX.PROPARHCSDX.PRO
X-RAY DIFFRACTION2TOPH19.SOLPARAM19.SOL
X-RAY DIFFRACTION3TOPH19X.HEMEPARAM19X.HEME
X-RAY DIFFRACTION4A2.TOPA2.PAR
X-RAY DIFFRACTION5MISC.TOPMISC.PAR
X-RAY DIFFRACTION6

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