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- PDB-3e7g: Structure of human INOSOX with inhibitor AR-C95791 -

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Basic information

Entry
Database: PDB / ID: 3e7g
TitleStructure of human INOSOX with inhibitor AR-C95791
ComponentsNitric oxide synthase, inducible
KeywordsOXIDOREDUCTASE / nitric oxide / NOS / HEME / tetrahydrobiopterin / Alternative splicing / Calcium / Calmodulin-binding / FAD / FMN / Iron / Metal-binding / NADP / Phosphoprotein / Polymorphism / Zinc
Function / homology
Function and homology information


positive regulation of leukocyte mediated cytotoxicity / Inhibition of nitric oxide production / peptidyl-cysteine S-nitrosylation / regulation of cellular respiration / Nitric oxide stimulates guanylate cyclase / prostaglandin secretion / ROS and RNS production in phagocytes / tetrahydrobiopterin binding / arginine binding / superoxide metabolic process ...positive regulation of leukocyte mediated cytotoxicity / Inhibition of nitric oxide production / peptidyl-cysteine S-nitrosylation / regulation of cellular respiration / Nitric oxide stimulates guanylate cyclase / prostaglandin secretion / ROS and RNS production in phagocytes / tetrahydrobiopterin binding / arginine binding / superoxide metabolic process / regulation of cytokine production involved in inflammatory response / cortical cytoskeleton / Fc-gamma receptor signaling pathway involved in phagocytosis / peroxisomal matrix / nitric oxide mediated signal transduction / nitric-oxide synthase (NADPH) / nitric-oxide synthase activity / L-arginine catabolic process / negative regulation of blood pressure / response to hormone / nitric oxide biosynthetic process / regulation of insulin secretion / cell redox homeostasis / innate immune response in mucosa / positive regulation of interleukin-8 production / response to bacterium / Peroxisomal protein import / 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 / Interleukin-4 and Interleukin-13 signaling / response to lipopolysaccharide / defense response to Gram-negative bacterium / 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 / nucleoplasm / metal ion binding / nucleus / plasma membrane / 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
Chem-AT2 / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase, inducible
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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 18, 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 / Item: _software.name
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_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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 / _struct_conn.ptnr2_label_seq_id / _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
B: Nitric oxide synthase, inducible
C: Nitric oxide synthase, inducible
D: Nitric oxide synthase, inducible
hetero molecules


Theoretical massNumber of molelcules
Total (without water)200,81518
Polymers196,1994
Non-polymers4,61514
Water9,080504
1
A: Nitric oxide synthase, inducible
B: Nitric oxide synthase, inducible
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,4079
Polymers98,1002
Non-polymers2,3087
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5410 Å2
ΔGint-34 kcal/mol
Surface area35540 Å2
MethodPISA
2
C: Nitric oxide synthase, inducible
D: Nitric oxide synthase, inducible
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,4079
Polymers98,1002
Non-polymers2,3087
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5340 Å2
ΔGint-36 kcal/mol
Surface area35570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)90.206, 158.671, 191.141
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 49049.863 Da / Num. of mol.: 4 / Fragment: UNP residues 82-505
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: P35228, nitric-oxide synthase (NADPH)

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Non-polymers , 5 types, 518 molecules

#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#4: Chemical
ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN


Mass: 241.247 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H15N5O3
#5: Chemical
ChemComp-AT2 / ETHYL 4-[(4-METHYLPYRIDIN-2-YL)AMINO]PIPERIDINE-1-CARBOXYLATE


Mass: 263.335 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H21N3O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 504 / 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: 3.48 Å3/Da / Density % sol: 64.42 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 7
Details: magnesium sulfate, hepes, lithium acetate, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-BM-C / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Sep 24, 1999
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→40 Å / Num. obs: 141544 / % possible obs: 88.4 % / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.077
Reflection shellResolution: 2.1→2.18 Å / Rmerge(I) obs: 0.327 / % possible all: 51.1

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Processing

Software
NameVersionClassificationNB
CNS0.9refinement
PDB_EXTRACT3.006data extraction
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.2→39.51 Å / Rfactor Rfree error: 0.003 / Occupancy max: 1 / Occupancy min: 1 / Data cutoff high absF: 262227 / 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
Rfree0.213 6396 5.1 %RANDOM
Rwork0.182 ---
obs-125869 90.2 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 53.18 Å2 / ksol: 0.33 e/Å3
Displacement parametersBiso max: 107.92 Å2 / Biso mean: 49.211 Å2 / Biso min: 23.75 Å2
Baniso -1Baniso -2Baniso -3
1--9.42 Å20 Å20 Å2
2--10.94 Å20 Å2
3----1.51 Å2
Refinement stepCycle: LAST / Resolution: 2.2→39.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13694 0 318 504 14516
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.009
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d22.9
X-RAY DIFFRACTIONc_improper_angle_d0.95
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
LS refinement shellResolution: 2.2→2.34 Å / Rfactor Rfree error: 0.01 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.294 818 5.1 %
Rwork0.258 15110 -
all-15928 -
obs--69.4 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.TOPPROTEIN_REP.PARAM
X-RAY DIFFRACTION2TOPH19X.HEMEPARAM19X.HEME
X-RAY DIFFRACTION3A1.TOPA1.PAR
X-RAY DIFFRACTION4

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