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- PDB-2orp: Murine inducible nitric oxide synthase oxygenase domain (delta 11... -

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Basic information

Entry
Database: PDB / ID: 2orp
TitleMurine inducible nitric oxide synthase oxygenase domain (delta 114) 2-[4-(2-Imidazol-1-yl-6-methyl-pyrimidin-4-yl)-1-isobutyryl-piperazin-2-yl]-N-[2-(4-methoxy-phenyl)-ethyl]-acetamide 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 / 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 / flavin adenine dinucleotide binding / NADP 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
PROTOPORPHYRIN IX CONTAINING FE / Chem-R86 / Nitric oxide synthase, inducible
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.97 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. / Arnaiz, D. / Eagen, K. / Erickson, S. / Guilford, W. / Kenrick, M. / Morrissey, M.M. / Ohlmeyer, M. / Pan, G. / Paradkar, V.M. / Parkinson, J. / Polokoff, M. / ...Authors: Davey, D.D. / Adler, M. / Arnaiz, D. / Eagen, K. / Erickson, S. / Guilford, W. / Kenrick, M. / Morrissey, M.M. / Ohlmeyer, M. / Pan, G. / Paradkar, V.M. / Parkinson, J. / Polokoff, M. / Saionz, K. / Santos, C. / Subramanyam, B. / Vergona, R. / Wei, R.G. / Whitlow, M. / Ye, B. / Zhao, Z.S. / Devlin, J.J. / Phillips, G.
#1: 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. / Eagan, K.A. / Erickson, S. / Glaser, C. / Mallari, C. / Morrissey, ...Authors: Mcmillan, K. / Adler, M. / Auld, D.S. / Baldwin, J.J. / Blasko, E. / Browne, L.J. / Chelsky, D. / Davey, D. / Dolle, R.E. / Eagan, K.A. / Erickson, S. / Glaser, C. / Mallari, C. / Morrissey, M.M. / Ohlmeyer, M.H.J. / Pan, G. / Parkinson, J.F. / Phillips, G.B. / Polokoff, M.A. / Sigal, N.H. / Vergona, R. / Whitlow, M. / Devl, J.J.
#2: 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.
#3: 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 10, 2007Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 30, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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

Downloads & links

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Assembly

Deposited unit
A: nitric oxide synthase, inducible
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,3923
Polymers45,2701
Non-polymers1,1222
Water3,621201
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)63.230, 73.750, 93.560
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 / E.C.1.14.13.39 / NOS type II / Inducible NO synthase / Inducible NOS / iNOS / Macrophage NOS / MAC- NOS


Mass: 45270.379 Da / Num. of mol.: 1 / Fragment: OXYGENASE DOMAIN, RESIDUES 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


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-R86 / 2-{(2R)-4-[2-(1H-IMIDAZOL-1-YL)-6-METHYLPYRIMIDIN-4-YL]-1-ISOBUTYRYLPIPERAZIN-2-YL}-N-[2-(4-METHOXYPHENYL)ETHYL]ACETAMIDE


Mass: 505.612 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H35N7O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 201 / 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: 2.41 Å3/Da / Density % sol: 48.92 %
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 1) 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 1) 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 2-[4-(2-Imidazol-1-yl-6- methyl-pyrimidin-4-yl)-1-isobutyryl-piperazin-2-yl]-N- [2-(4-methoxy-phenyl)-ethyl]-acetamide, 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: SSRL / Beamline: BL7-1 / Wavelength: 1.08 / Wavelength: 1.08 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Apr 9, 1998
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.08 Å / Relative weight: 1
ReflectionResolution: 1.97→19.75 Å / Num. all: 29604 / Num. obs: 21034 / % possible obs: 95.3 % / Observed criterion σ(I): 1 / Redundancy: 3.6 % / Biso Wilson estimate: 20.9 Å2 / Rmerge(I) obs: 0.09 / Net I/σ(I): 5.4
Reflection shellResolution: 1.97→2.08 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.289 / Mean I/σ(I) obs: 2.5 / % possible all: 95.3

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Processing

Software
NameVersionClassification
Blu-Icedata collection
X-PLORmodel building
CNS1.1refinement
Blu-Icedata collection
MOSFLMdata reduction
CCP4(SCALA)data scaling
X-PLORphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1NOS

1nos


Resolution: 1.97→19.75 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 1664513.05 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
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 1179 4 %RANDOM
Rwork0.217 ---
all0.218 29604 --
obs-21034 93.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 78.2787 Å2 / ksol: 0.401889 e/Å3
Displacement parametersBiso mean: 36.1 Å2
Baniso -1Baniso -2Baniso -3
1--5.5 Å20 Å20 Å2
2--6.85 Å20 Å2
3----1.34 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.28 Å0.23 Å
Luzzati d res low-5 Å
Luzzati sigma a0.14 Å0.15 Å
Refinement stepCycle: LAST / Resolution: 1.97→19.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2476 0 80 201 2757
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_deg0.9
X-RAY DIFFRACTIONc_dihedral_angle_d20.6
X-RAY DIFFRACTIONc_improper_angle_d0.79
X-RAY DIFFRACTIONc_mcbond_it1.551.5
X-RAY DIFFRACTIONc_mcangle_it2.542
X-RAY DIFFRACTIONc_scbond_it2.152
X-RAY DIFFRACTIONc_scangle_it3.293
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection Rfree% reflection Rfree (%)Rfactor RworkNum. reflection RworkRfactor Rfree errorNum. reflection obs% reflection obs (%)
1.97-2.040.2611004.10.271523650.026246579
2.04-2.120.32721150.23172916
2.12-2.220.24461300.20642926
2.22-2.340.25431440.21452906
2.34-2.480.20681450.20332918
2.48-2.670.21261210.20062943
2.67-2.940.25771230.2122927
2.94-3.360.2711000.22072965
3.36-4.230.249940.20162923
4.23-19.750.26031064.10.236123652615
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 DIFFRACTION4R86.parR86.top

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