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- PDB-2orr: Murine Inducible Nitric Oxide Synthase Oxygenase Domain (Delta 11... -

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Entry
Database: PDB / ID: 2orr
TitleMurine Inducible Nitric Oxide Synthase Oxygenase Domain (Delta 114) 4-(Benzo[1,3]dioxol-5-yloxy)-2-(4-imidazol-1-yl-phenoxy)-pyrimidine Complex
ComponentsNitric oxide synthase, inducible
KeywordsOXIDOREDUCTASE / NITRIC OXIDE / L-ARGININE MONOOXYGENASE / HEME / DIMERIZATION / INHIBITOR / NOS
Function / homology
Function and homology information


Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / G protein-coupled receptor signaling pathway coupled to cGMP nucleotide second messenger / Peroxisomal protein import / cAMP-dependent protein kinase regulator activity / prostaglandin secretion / positive regulation of killing of cells of another organism / tetrahydrobiopterin binding / arginine binding / cortical cytoskeleton ...Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / G protein-coupled receptor signaling pathway coupled to cGMP nucleotide second messenger / Peroxisomal protein import / cAMP-dependent protein kinase regulator activity / prostaglandin secretion / positive regulation of killing of cells of another organism / tetrahydrobiopterin binding / arginine binding / cortical cytoskeleton / superoxide metabolic process / cGMP-mediated signaling / nitric-oxide synthase binding / cellular response to cytokine stimulus / regulation of cytokine production involved in inflammatory response / peptidyl-cysteine S-nitrosylation / regulation of insulin secretion / cellular response to organic cyclic compound / blood vessel remodeling / nitric-oxide synthase (NADPH) / response to tumor necrosis factor / nitric-oxide synthase activity / nitric oxide mediated signal transduction / arginine catabolic process / negative regulation of blood pressure / nitric oxide biosynthetic process / response to hormone / positive regulation of interleukin-8 production / response to bacterium / negative regulation of protein catabolic process / Hsp90 protein binding / cellular response to type II interferon / regulation of blood pressure / beta-catenin binding / positive regulation of interleukin-6 production / peroxisome / circadian rhythm / cellular response to xenobiotic stimulus / FMN binding / flavin adenine dinucleotide binding / regulation of cell population proliferation / NADP binding / actin binding / cellular response to lipopolysaccharide / response to lipopolysaccharide / response to hypoxia / calmodulin binding / intracellular signal transduction / defense response to bacterium / cadherin binding / inflammatory response / positive regulation of apoptotic process / negative regulation of gene expression / heme binding / protein kinase binding / perinuclear region of cytoplasm / protein homodimerization activity / extracellular space / metal ion binding / nucleus / identical protein binding / plasma membrane / cytosol / cytoplasm
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, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 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, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain 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
Chem-333 / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase, inducible
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsAdler, M. / Whitlow, M.
Citation
Journal: J.Med.Chem. / Year: 2007
Title: Design, Synthesis, and Activity of 2-Imidazol-1-ylpyrimidine Derived Inducible Nitric Oxide Synthase Dimerization Inhibitors
Authors: Davey, D.D. / Adler, M. / Arnaia, D. / Eagen, K. / Erickson, S. / Guilford, W. / Kenrick, M. / Morrissey, M.M. / Ohimeyer, M. / Pan, G. / Paradkar, V.M. / Parkinson, J. / Polokoff, M. / ...Authors: Davey, D.D. / Adler, M. / Arnaia, D. / Eagen, K. / Erickson, S. / Guilford, W. / Kenrick, M. / Morrissey, M.M. / Ohimeyer, M. / Pan, G. / Paradkar, V.M. / Parkinson, J. / Polokoff, M. / Salonz, K. / Santos, C. / Subramanyam, B. / Vergona, R. / Wei, R.G. / Whitlow, M. / Ye, B. / Zhao, Z.S. / Devlin, J.J. / Phillips, G.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2007
Title: The Rational Design of Inhibitors of Nitric Oxide Formation by Inducible Nitric Oxide Synthase
Authors: Whitlow, M. / Adler, M. / Davey, D.D. / Huang, Q. / Koovakkat, S. / Pham, E. / Polokoff, M. / Xu, W. / Yuan, S.S. / Phillips, G.
#2: Journal: To be Published / Year: 2007
Title: 3-[4-(1-Imidazolyl)phenoxy]-1-piperonyl Piperidine Analogs as Potent and Selective Inhibitors of Nitric Oxide Formation
Authors: Wei, R.G. / Adler, M. / Davey, D. / Ho, E. / Mohan, R. / Polokoff, M. / Tseng, J.L. / Whitlow, M. / Xu, W. / Yuan, S. / Phillips, G.
#3: Journal: Proc.Natl.Acad.Sci.USA / Year: 2000
Title: Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry.
Authors: McMillan, K. / Adler, M. / Auld, D.S. / Baldwin, J.J. / Blasko, E. / Browne, L.J. / Chelsky, D. / Davey, D. / Dolle, R.E. / Eagen, K.A. / Erickson, S. / Feldman, R.I. / Glaser, C.B. / ...Authors: McMillan, K. / Adler, M. / Auld, D.S. / Baldwin, J.J. / Blasko, E. / Browne, L.J. / Chelsky, D. / Davey, D. / Dolle, R.E. / Eagen, K.A. / Erickson, S. / Feldman, R.I. / Glaser, C.B. / Mallari, C. / Morrissey, M.M. / Ohlmeyer, M.H. / Pan, G. / Parkinson, J.F. / Phillips, G.B. / Polokoff, M.A. / Sigal, N.H. / Vergona, R. / Whitlow, M. / Young, T.A. / Devlin, J.J.
#4: Journal: Science / Year: 1997
Title: The structure of nitric oxide synthase oxygenase domain and inhibitor complexes.
Authors: Crane, B.R. / Arvai, A.S. / Gachhui, R. / Wu, C. / Ghosh, D.K. / Getzoff, E.D. / Stuehr, D.J. / Tainer, J.A.
#5: Journal: Biochemistry / Year: 1997
Title: Characterization of the inducible nitric oxide synthase oxygenase domain identifies a 49 amino acid segment required for subunit dimerization and tetrahydrobiopterin interaction.
Authors: Ghosh, D.K. / Wu, C. / Pitters, E. / Moloney, M. / Werner, E.R. / Mayer, B. / Stuehr, D.J.
History
DepositionFeb 4, 2007Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 17, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,5097
Polymers45,2701
Non-polymers1,2396
Water2,450136
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A: Nitric oxide synthase, inducible
hetero molecules

A: Nitric oxide synthase, inducible
hetero molecules


Theoretical massNumber of molelcules
Total (without water)93,01914
Polymers90,5412
Non-polymers2,47812
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_546x+1/2,-y-1/2,-z+11
Unit cell
Length a, b, c (Å)63.403, 74.048, 93.253
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 45270.379 Da / Num. of mol.: 1 / Fragment: OXYGENASE DOMAIN 114-498
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Nos2, Inosl / Plasmid: PCWORI / Production host: Escherichia coli (E. coli) / References: UniProt: P29477, nitric-oxide synthase (NADPH)
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-333 / 4-(1,3-BENZODIOXOL-5-YLOXY)-2-[4-(1H-IMIDAZOL-1-YL)PHENOXY]PYRIMIDINE


Mass: 374.350 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H14N4O4
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 136 / 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: 2.42 Å3/Da / Density % sol: 49.1 %
Crystal growTemperature: 308 K / Method: vapor diffusion, hanging drop / pH: 4.7
Details: CRYSTALS OF MURINE DELTA114 INOS WERE PREPARED IN THE PRESENCE OF IMIDAZOLE FOLLOWING THE PROCEDURES OF CRANE ET AL. (REFERENCE 3) AS FOLLOWS: THE 6 UL CRYSTALLIZATION DROPS CONTAINED 20 ...Details: CRYSTALS OF MURINE DELTA114 INOS WERE PREPARED IN THE PRESENCE OF IMIDAZOLE FOLLOWING THE PROCEDURES OF CRANE ET AL. (REFERENCE 3) AS FOLLOWS: THE 6 UL CRYSTALLIZATION DROPS CONTAINED 20 MG/ML MURINE DELTA114 INOS, 20 MM HEPES PH 7.6, 5 % GLYCEROL, 0.5 MM DTT, 6.8 % PEG-3350, 60 MM NA2SO3, AND 50 MM IMIDAZOLE/ MALATE BUFFER PH 4.7 WERE PLACED OVER A 1 ML RESERVOIR CONTAINING 13.6 % PEG-3350, 120 MM NA2SO3, AND 100 MM IMIDAZOLE/MALATE BUFFER PH 4.7. THESE CRYSTALS WERE SOAKED FOR 25 HOURS IN 5 UM 4-(Benzo[1,3]dioxol-5-yloxy)- 2-(4-imidazol-1-yl-phenoxy)-pyrimidine, 14 % PEG-3350, 1 MM NAN3, 50 MM MES PH 6.5 AND 50 MM NA2SO3. THE, pH 4.70, VAPOR DIFFUSION, HANGING DROP, temperature 308K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Aug 10, 1998
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength
IDWavelength (Å)Relative weight
111
211
ReflectionResolution: 1.9→30 Å / Num. obs: 33547 / % possible obs: 95.06 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.21 % / Biso Wilson estimate: 28.3 Å2 / Rsym value: 0.0607 / Net I/σ(I): 16.82
Reflection shellResolution: 1.9→1.96 Å / Redundancy: 2.55 % / Rmerge(I) obs: 0.34 / Mean I/σ(I) obs: 1.5 / % possible all: 74.4

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Processing

Software
NameVersionClassification
X-PLORmodel building
CNX2005refinement
ADSCQUANTUMdata collection
X-GENdata reduction
X-GENdata scaling
X-PLORphasing
CNS1.1refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB Entry BX04

Resolution: 2→29.14 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 221896.26 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / σ(I): 0
Details: ATOMS WITH NO 1.0 SIGMA 2FO-FC DENSITY HAD THEIR OCCUPANCY LOWERED TO 0.5. THE POSITION OF THESE ATOMS SHOULD NOT BE TRUSTED.
RfactorNum. reflection% reflectionSelection details
Rfree0.252 1093 4 %RANDOM
Rwork0.222 ---
all0.223 ---
obs-26997 88.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 55.6954 Å2 / ksol: 0.333673 e/Å3
Displacement parametersBiso mean: 43.5 Å2
Baniso -1Baniso -2Baniso -3
1--14.46 Å20 Å20 Å2
2--14.76 Å20 Å2
3----0.3 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.28 Å0.24 Å
Luzzati d res low-5 Å
Luzzati sigma a0.22 Å0.19 Å
Refinement stepCycle: LAST / Resolution: 2→29.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2380 0 87 136 2603
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d20.7
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.9
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.581.5
X-RAY DIFFRACTIONc_mcangle_it2.512
X-RAY DIFFRACTIONc_scbond_it2.182
X-RAY DIFFRACTIONc_scangle_it3.313
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 8

Resolution (Å)Rfactor RfreeNum. reflection Rfree% reflection Rfree (%)Rfactor RworkNum. reflection RworkRfactor Rfree errorNum. reflection obs% reflection obs (%)
2-2.090.32671084.30.268423950.031237367.3
2.09-2.20.29561350.24182889
2.2-2.340.28291250.23123094
2.34-2.520.26131560.22193245
2.52-2.770.25091390.21723410
2.77-3.170.23531340.2143487
3.17-40.22261310.20133601
4-29.140.25591650.23323805
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.pprotein.top
X-RAY DIFFRACTION2water_rep.parwater.top
X-RAY DIFFRACTION3HEM.parHEM.top
X-RAY DIFFRACTION4EGL.parEGL.top
X-RAY DIFFRACTION5336.par336.top

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