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- PDB-6pn9: Structure of rat neuronal nitric oxide synthase heme domain in co... -

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Basic information

Entry
Database: PDB / ID: 6pn9
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with 7-(3-(Aminomethyl)-4-(thiazol-5-ylmethoxy)phenyl)-4-methylquinolin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/Inhibitor / nitric oxide synthase inhibitor / heme enzyme / OXIDOREDUCTASE / OXIDOREDUCTASE-Inhibitor complex
Function / homology
Function and homology information


negative regulation of hepatic stellate cell contraction / retrograde trans-synaptic signaling by nitric oxide / Nitric oxide stimulates guanylate cyclase / positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / azurophil granule / positive regulation of sodium ion transmembrane transport / negative regulation of vasoconstriction ...negative regulation of hepatic stellate cell contraction / retrograde trans-synaptic signaling by nitric oxide / Nitric oxide stimulates guanylate cyclase / positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / azurophil granule / positive regulation of sodium ion transmembrane transport / negative regulation of vasoconstriction / peptidyl-cysteine S-nitrosylation / postsynaptic specialization, intracellular component / nitric oxide metabolic process / negative regulation of cytosolic calcium ion concentration / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / Ion homeostasis / response to nitric oxide / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of potassium ion transport / negative regulation of calcium ion transport / behavioral response to cocaine / nitric oxide mediated signal transduction / regulation of neurogenesis / nitric-oxide synthase (NADPH) / negative regulation of serotonin uptake / sodium channel regulator activity / response to vitamin E / regulation of postsynaptic membrane potential / nitric-oxide synthase activity / postsynaptic density, intracellular component / multicellular organismal response to stress / arginine catabolic process / negative regulation of insulin secretion / xenobiotic catabolic process / NADPH binding / striated muscle contraction / regulation of sodium ion transport / nitric oxide-cGMP-mediated signaling / negative regulation of blood pressure / response to hormone / T-tubule / photoreceptor inner segment / cellular response to epinephrine stimulus / sarcoplasmic reticulum membrane / nitric oxide biosynthetic process / calyx of Held / sarcoplasmic reticulum / secretory granule / positive regulation of long-term synaptic potentiation / cell periphery / response to activity / female pregnancy / establishment of localization in cell / phosphoprotein binding / response to nicotine / establishment of protein localization / response to lead ion / response to nutrient levels / potassium ion transport / sarcolemma / cellular response to growth factor stimulus / : / caveola / response to peptide hormone / Z disc / cellular response to mechanical stimulus / response to estrogen / vasodilation / calcium-dependent protein binding / calcium ion transport / FMN binding / NADP binding / flavin adenine dinucleotide binding / ATPase binding / response to heat / scaffold protein binding / nuclear membrane / response to ethanol / response to lipopolysaccharide / negative regulation of neuron apoptotic process / dendritic spine / mitochondrial outer membrane / transmembrane transporter binding / response to hypoxia / cytoskeleton / calmodulin binding / postsynaptic density / membrane raft / negative regulation of cell population proliferation / dendrite / heme binding / synapse / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / glutamatergic synapse / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex
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 / PDZ domain / Flavoprotein-like superfamily / PDZ domain profile. / Domain present in PSD-95, Dlg, and ZO-1/2. / PDZ domain / PDZ superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
ACETATE ION / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-OU7 / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.84 Å
AuthorsLi, H. / Poulos, T.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)GM57353 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.
Authors: Cinelli, M.A. / Reidl, C.T. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionJul 2, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1May 27, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)100,27711
Polymers97,6252
Non-polymers2,6529
Water6,864381
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9760 Å2
ΔGint-84 kcal/mol
Surface area33410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.870, 111.690, 164.140
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, 2 molecules AB

#1: Protein Nitric oxide synthase, brain / BNOS / Constitutive NOS / NC-NOS / NOS type I / Neuronal NOS / nNOS / Peptidyl-cysteine S-nitrosylase NOS1


Mass: 48812.527 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Nos1, Bnos / Organ: brain / Plasmid: pCWori / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P29476, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 390 molecules

#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 / Comment: neurotransmitter*YM
#4: Chemical ChemComp-OU7 / 7-{3-(aminomethyl)-4-[(1,3-thiazol-5-yl)methoxy]phenyl}-4-methylquinolin-2-amine


Mass: 376.475 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H20N4OS / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 381 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.48 Å3/Da / Density % sol: 50.4 % / Description: bricks
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.8
Details: 20-24% PEG3350, 0.1M MES 0.14-0.20M AMMONIUM ACETATE, 10% ETHYLENE GLYCOL, 30uM SDS, 5 mM GSH

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 1.195 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jul 12, 2018 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.195 Å / Relative weight: 1
ReflectionResolution: 1.84→67 Å / Num. obs: 83551 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 5.3 % / CC1/2: 0.996 / Rmerge(I) obs: 0.124 / Rpim(I) all: 0.089 / Rsym value: 0.124 / Net I/σ(I): 5.2
Reflection shellResolution: 1.84→1.89 Å / Redundancy: 5.5 % / Rmerge(I) obs: 3.388 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 4509 / CC1/2: 0.568 / Rpim(I) all: 2.446 / Rsym value: 3.388 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.11.1-2575_1496: ???)refinement
MOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1OM4

1om4


Resolution: 1.84→66.135 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 36.47
RfactorNum. reflection% reflectionSelection details
Rfree0.2532 7821 4.95 %random
Rwork0.2103 ---
obs0.2125 83130 98.79 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.84→66.135 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6691 0 183 381 7255
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087121
X-RAY DIFFRACTIONf_angle_d0.9969693
X-RAY DIFFRACTIONf_dihedral_angle_d17.4974139
X-RAY DIFFRACTIONf_chiral_restr0.049999
X-RAY DIFFRACTIONf_plane_restr0.0061222
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.84-1.86090.42452690.42995064X-RAY DIFFRACTION100
1.8609-1.88280.49712450.43085027X-RAY DIFFRACTION99
1.8828-1.90580.48572330.40775053X-RAY DIFFRACTION99
1.9058-1.92990.44422740.40435022X-RAY DIFFRACTION99
1.9299-1.95530.45682660.40115005X-RAY DIFFRACTION99
1.9553-1.98210.43293170.37875008X-RAY DIFFRACTION99
1.9821-2.01040.40942470.37144999X-RAY DIFFRACTION99
2.0104-2.04040.41432280.36564962X-RAY DIFFRACTION98
2.0404-2.07230.4192730.36245028X-RAY DIFFRACTION98
2.0723-2.10630.42652510.34834940X-RAY DIFFRACTION98
2.1063-2.14260.3632060.32484980X-RAY DIFFRACTION97
2.1426-2.18160.39552180.31234854X-RAY DIFFRACTION95
2.1816-2.22350.3292680.29054937X-RAY DIFFRACTION98
2.2235-2.26890.33092680.28475019X-RAY DIFFRACTION99
2.2689-2.31830.31443060.26914989X-RAY DIFFRACTION99
2.3183-2.37220.30682620.25565056X-RAY DIFFRACTION99
2.3722-2.43150.3712610.25335003X-RAY DIFFRACTION99
2.4315-2.49730.33352420.2475095X-RAY DIFFRACTION100
2.4973-2.57080.30762590.2345021X-RAY DIFFRACTION99
2.5708-2.65370.31972560.24045027X-RAY DIFFRACTION99
2.6537-2.74860.30572710.24665013X-RAY DIFFRACTION99
2.7486-2.85860.29542360.23645033X-RAY DIFFRACTION99
2.8586-2.98870.25712690.21744929X-RAY DIFFRACTION97
2.9887-3.14630.24592870.20664848X-RAY DIFFRACTION97
3.1463-3.34340.22922490.18645058X-RAY DIFFRACTION100
3.3434-3.60160.18922660.16155071X-RAY DIFFRACTION100
3.6016-3.9640.18872650.14545090X-RAY DIFFRACTION100
3.964-4.53740.17152750.13095020X-RAY DIFFRACTION100
4.5374-5.71620.18553050.1394911X-RAY DIFFRACTION98
5.7162-66.1780.18272490.16195014X-RAY DIFFRACTION99
Refinement TLS params.

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

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.0086-0.2354-0.25331.29980.09467.2088-0.05390.156-0.0083-0.0293-0.10210.0771-0.089-0.38180.09330.36050.00620.00650.302-0.0030.274411.20684.901822.5723
21.0676-0.282-0.18741.25070.39093.6263-0.0043-0.04210.0367-0.1034-0.0609-0.04060.15210.15420.04590.24890.00140.04060.25740.02040.243112.48984.899659.9574
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 299:716)
2X-RAY DIFFRACTION2(chain B and resid 299:718)

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