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- PDB-4cx7: Structure of human iNOS heme domain in complex with (R)-6-(3-AMIN... -

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Basic information

Entry
Database: PDB / ID: 4cx7
TitleStructure of human iNOS heme domain in complex with (R)-6-(3-AMINO-2-(5-(2-(6-AMINO-4- METHYLPYRIDIN-2-YL)ETHYL)PYRIDIN-3-YL)PROPYL)-4- METHYLPYRIDIN-2-AMINE
ComponentsNITRIC OXIDE SYNTHASE, INDUCIBLE
KeywordsOXIDOREDUCTASE / INHIBITOR COMPLEX
Function / homology
Function and homology information


positive regulation of leukocyte mediated cytotoxicity / Inhibition of nitric oxide production / prostaglandin secretion / Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / regulation of cellular respiration / positive regulation of killing of cells of another organism / tetrahydrobiopterin binding / arginine binding / cortical cytoskeleton ...positive regulation of leukocyte mediated cytotoxicity / Inhibition of nitric oxide production / prostaglandin secretion / Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / regulation of cellular respiration / positive regulation of killing of cells of another organism / tetrahydrobiopterin binding / arginine binding / cortical cytoskeleton / superoxide metabolic process / regulation of cytokine production involved in inflammatory response / peptidyl-cysteine S-nitrosylation / peroxisomal matrix / regulation of insulin secretion / nitric-oxide synthase (NADPH) / positive regulation of guanylate cyclase activity / negative regulation of blood pressure / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen / nitric oxide mediated signal transduction / vesicle membrane / nitric-oxide synthase activity / innate immune response in mucosa / arginine catabolic process / response to hormone / cellular response to interferon-gamma / nitric oxide biosynthetic process / cell redox homeostasis / response to bacterium / Peroxisomal protein import / positive regulation of interleukin-8 production / positive regulation of interleukin-6 production / peroxisome / negative regulation of protein catabolic process / circadian rhythm / cellular response to xenobiotic stimulus => GO:0071466 / regulation of cell population proliferation / FMN binding / flavin adenine dinucleotide binding / NADP binding / response to lipopolysaccharide / Interleukin-4 and Interleukin-13 signaling / calmodulin binding / response to hypoxia / cellular response to lipopolysaccharide / inflammatory response / defense response to Gram-negative bacterium / oxidoreductase activity / negative regulation of gene expression / defense response to bacterium / heme binding / perinuclear region of cytoplasm / protein homodimerization activity / nucleoplasm / plasma membrane / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Nitric-oxide synthase, eukaryote / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / 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, oxygenase domain / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain superfamily ...Nitric-oxide synthase, eukaryote / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / 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, oxygenase domain / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain superfamily / 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 / Oxidoreductase FAD/NAD(P)-binding / Oxidoreductase NAD-binding domain / Flavodoxin-like domain profile. / Flavodoxin/nitric oxide synthase / Ferredoxin-NADP reductase (FNR), nucleotide-binding domain / Ferredoxin reductase-type FAD binding domain profile. / FAD-binding domain, ferredoxin reductase-type / Riboflavin synthase-like beta-barrel / Flavoprotein-like superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-S71 / Nitric oxide synthase, inducible
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.16 Å
AuthorsLi, H. / Poulos, T.L.
CitationJournal: Biochemistry / Year: 2014
Title: Mobility of a Conserved Tyrosine Residue Controls Isoform-Dependent Enzyme-Inhibitor Interactions in Nitric Oxide Synthases.
Authors: Li, H. / Jamal, J. / Delker, S.L. / Plaza, C. / Ji, H. / Jing, Q. / Huang, H. / Kang, S. / Silverman, R.B. / Poulos, T.L.
History
DepositionApr 3, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 13, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 3, 2014Group: Database references

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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)204,99229
Polymers198,8224
Non-polymers6,17025
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area19490 Å2
ΔGint-258.5 kcal/mol
Surface area66780 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)189.223, 189.223, 232.773
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C
12B
22D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1114A83 - 502
2114C83 - 502
1124B83 - 502
2124D83 - 502

NCS ensembles :
ID
1
2

NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2given(-0.998824, 0.011623, 0.047074), (-0.01744, -0.991989, -0.125114), (0.045242, -0.125787, 0.991025)1.8595, -182.22885, -23.50061
3given(-0.99787, 0.023822, 0.060736), (-0.030627, -0.993044, -0.113692), (0.057605, -0.11531, 0.991658)2.69632, -182.64061, -22.49474

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
NITRIC OXIDE SYNTHASE, INDUCIBLE / / HEPATOCYTE NOS / HEP-NOS / INDUCIBLE NO SYNTHASE / INDUCIBLE NOS / INOS / NOS TYPE II / PEPTIDYL- ...HEPATOCYTE NOS / HEP-NOS / INDUCIBLE NO SYNTHASE / INDUCIBLE NOS / INOS / NOS TYPE II / PEPTIDYL-CYSTEINE S-NITROSYLASE NOS2 / INDUCIBLE NITRIC OXIDE SYNTHASE


Mass: 49705.531 Da / Num. of mol.: 4 / Fragment: HEME DOMAIN, RESIDUES 74-504
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P35228, nitric-oxide synthase (NADPH)

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Non-polymers , 5 types, 25 molecules

#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


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


Mass: 241.247 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#4: Chemical
ChemComp-S71 / (R)-6-(3-amino-2-(5-(2-(6-amino-4-methylpyridin-2-yl)ethyl)pyridin-3-yl)propyl)-4-methylpyridin-2-amine


Mass: 376.498 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H28N6
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: SO4

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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: 5.4 Å3/Da / Density % sol: 77.3 %
Description: R-MERGE 0.23 R-PIM 0.07 CC ONE-HALF 99.6 HIGHEST RESOLUTION SHELL R-MERGE 1.863 R-PIM 0.582 CC ONE-HALF 49.3
Crystal growpH: 6
Details: 1.3M AMMONIUM SULFATE, 50 MM NA CITRATE, PH5.0 30% GLYCEROL 5 MM GSH, pH 6.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.979
DetectorType: DECTRIS PILATUS / Detector: PIXEL / Date: Jul 29, 2013 / Details: MIRRORS
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 3.16→50 Å / Num. obs: 72855 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 11.9 % / Rmerge(I) obs: 0.23 / Net I/σ(I): 12.6
Reflection shellResolution: 3.16→3.33 Å / Redundancy: 10.9 % / Rmerge(I) obs: 1.5 / Mean I/σ(I) obs: 1.5 / % possible all: 98.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1NSI
Resolution: 3.16→146.83 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.932 / SU B: 32.488 / SU ML: 0.256 / Cross valid method: THROUGHOUT / ESU R: 0.568 / ESU R Free: 0.312 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED FRAGMENT (RESIDUES 108 TO 114 IN EACH CHAIN) AROUND THE ZN BINDING SITE IS DISORDERED.
RfactorNum. reflection% reflectionSelection details
Rfree0.21622 3678 5.1 %RANDOM
Rwork0.17352 ---
obs0.17571 68962 99.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 78.317 Å2
Baniso -1Baniso -2Baniso -3
1--1.92 Å20 Å20 Å2
2---1.92 Å20 Å2
3---3.84 Å2
Refinement stepCycle: LAST / Resolution: 3.16→146.83 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13468 0 421 0 13889
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.01914308
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.951.9719482
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.48451644
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.33223.391696
X-RAY DIFFRACTIONr_dihedral_angle_3_deg23.086152296
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.28315104
X-RAY DIFFRACTIONr_chiral_restr0.1230.21985
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02111120
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.3354.8376600
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it5.2617.2498236
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.6965.2677708
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Number: 3367 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDTypeRms dev position (Å)Weight position
1Amedium positional0.350.5
2Bmedium positional0.290.5
1Amedium thermal4.742
2Bmedium thermal3.82
LS refinement shellResolution: 3.156→3.238 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.434 243 -
Rwork0.376 4738 -
obs--93.91 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
11.7007-0.00290.04131.86160.12911.9614-0.18220.16340.3441-0.10810.09110.1285-0.34-0.0240.09110.0904-0.0238-0.06310.07560.04090.0857-11.602-60.18715.702
21.9318-0.2319-0.32551.02760.1081.2018-0.1271-0.26920.04470.16580.05650.1982-0.007-0.0810.07070.15390.12270.04330.14550.02370.0693-19.814-68.09651.836
31.21230.2526-0.05191.4727-0.04041.7929-0.11560.4189-0.4109-0.4815-0.02490.01810.5541-0.25790.14050.6531-0.0176-0.03070.4193-0.10730.290613.088-126.15922.955
41.7805-0.43580.22871.7965-0.06531.2186-0.0211-0.039-0.15990.0995-0.0652-0.01110.2441-0.06360.08630.24960.0310.01130.05020.01960.040623.23-122.86759.312
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A82 - 502
2X-RAY DIFFRACTION2B82 - 502
3X-RAY DIFFRACTION3C82 - 502
4X-RAY DIFFRACTION4D82 - 502

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