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- PDB-9cvk: Structure of rat neuronal nitric oxide synthase R349A mutant heme... -

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Basic information

Entry
Database: PDB / ID: 9cvk
TitleStructure of rat neuronal nitric oxide synthase R349A mutant heme domain bound with 6-(3-chloro-5-((methylamino)methyl)phenyl)-4-methylpyridin-2-amine dihydrochloride
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor binding
Function / homology
Function and homology information


negative regulation of hepatic stellate cell contraction / 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 / response to vitamin B3 / azurophil granule / postsynaptic specialization, intracellular component / negative regulation of vasoconstriction ...negative regulation of hepatic stellate cell contraction / 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 / response to vitamin B3 / azurophil granule / postsynaptic specialization, intracellular component / negative regulation of vasoconstriction / negative regulation of cytosolic calcium ion concentration / Ion homeostasis / response to nitric oxide / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of sodium ion transmembrane transport / peptidyl-cysteine S-nitrosylase activity / regulation of postsynaptic membrane potential / cadmium ion binding / positive regulation of the force of heart contraction / behavioral response to cocaine / negative regulation of potassium ion transport / negative regulation of calcium ion transport / regulation of neurogenesis / nitric oxide mediated signal transduction / nitric-oxide synthase (NADPH) / sodium channel regulator activity / negative regulation of serotonin uptake / response to vitamin E / postsynaptic density, intracellular component / nitric-oxide synthase activity / multicellular organismal response to stress / xenobiotic catabolic process / L-arginine catabolic process / negative regulation of insulin secretion / NADPH binding / striated muscle contraction / regulation of sodium ion transport / nitric oxide-cGMP-mediated signaling / nitric oxide metabolic process / negative regulation of blood pressure / response to hormone / sarcoplasmic reticulum membrane / cellular response to epinephrine stimulus / photoreceptor inner segment / T-tubule / nitric oxide biosynthetic process / calyx of Held / secretory granule / sarcoplasmic reticulum / positive regulation of long-term synaptic potentiation / response to activity / cell periphery / 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 / response to estrogen / cellular response to mechanical stimulus / calcium ion transport / calcium-dependent protein binding / vasodilation / FMN binding / flavin adenine dinucleotide binding / NADP binding / ATPase binding / response to heat / scaffold protein binding / nuclear membrane / dendritic spine / negative regulation of neuron apoptotic process / response to lipopolysaccharide / response to ethanol / mitochondrial outer membrane / transmembrane transporter binding / cytoskeleton / response to hypoxia / calmodulin binding / postsynaptic density / membrane raft / negative regulation of cell population proliferation / synapse / heme binding / dendrite / 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
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 ...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
Similarity search - Domain/homology
: / ACETATE ION / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.901 Å
AuthorsLi, H. / Poulos, T.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM131920 United States
CitationJournal: Bioorg.Med.Chem. / Year: 2025
Title: Truncated pyridinylbenzylamines: Potent, selective, and highly membrane permeable inhibitors of human neuronal nitric oxide synthase.
Authors: Vasu, D. / Do, H.T. / Li, H. / Hardy, C.D. / Poulos, T.L. / Silverman, R.B.
History
DepositionJul 29, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 30, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,9706
Polymers48,7261
Non-polymers1,2445
Water75742
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.737, 113.321, 163.105
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-805-

ZN

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 48726.410 Da / Num. of mol.: 1 / Mutation: R349A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Nos1, Bnos / Organ: brain / Plasmid: pET22b / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P29476, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 47 molecules

#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-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN


Mass: 241.247 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#4: Chemical ChemComp-A1A0G / (6P)-6-{3-chloro-5-[(methylamino)methyl]phenyl}-4-methylpyridin-2-amine


Mass: 261.750 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H16ClN3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / 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.: 42 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 278 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: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 15, 2022 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→46.53 Å / Num. obs: 35691 / % possible obs: 99 % / Redundancy: 8.1 % / CC1/2: 0.998 / Rmerge(I) obs: 0.1 / Rpim(I) all: 0.034 / Rrim(I) all: 0.106 / Net I/σ(I): 8.3 / Num. measured all: 289665
Reflection shellResolution: 1.9→1.94 Å / % possible obs: 98 % / Redundancy: 6.1 % / Rmerge(I) obs: 6.546 / Num. measured all: 13799 / Num. unique obs: 2254 / CC1/2: 0.322 / Rpim(I) all: 2.832 / Rrim(I) all: 7.146 / Net I/σ(I) obs: 0.4

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1.11.1_2575refinement
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.901→46.53 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 0.06 / Phase error: 44.62 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2737 3213 5.03 %random
Rwork0.2187 ---
obs0.2216 33677 92.85 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.901→46.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3382 0 83 42 3507
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0063577
X-RAY DIFFRACTIONf_angle_d0.9984866
X-RAY DIFFRACTIONf_dihedral_angle_d18.5692083
X-RAY DIFFRACTIONf_chiral_restr0.051504
X-RAY DIFFRACTIONf_plane_restr0.005615
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.901-1.9290.5591010.45162209X-RAY DIFFRACTION75
1.9291-1.95920.44881350.44642127X-RAY DIFFRACTION76
1.9592-1.99130.45271210.4212282X-RAY DIFFRACTION80
1.9913-2.02570.4612990.41042280X-RAY DIFFRACTION80
2.0257-2.06250.47091030.42412413X-RAY DIFFRACTION84
2.0625-2.10220.47821290.392397X-RAY DIFFRACTION85
2.1022-2.14510.48181460.3852546X-RAY DIFFRACTION90
2.1451-2.19170.41381230.35932646X-RAY DIFFRACTION92
2.1917-2.24270.40031740.34092639X-RAY DIFFRACTION95
2.2427-2.29880.41371480.31182802X-RAY DIFFRACTION98
2.2988-2.36090.37971340.30692781X-RAY DIFFRACTION97
2.3609-2.43040.31291530.27922768X-RAY DIFFRACTION98
2.4304-2.50880.33821230.26492723X-RAY DIFFRACTION97
2.5088-2.59850.3321290.28572694X-RAY DIFFRACTION94
2.5985-2.70250.40131530.27462817X-RAY DIFFRACTION99
2.7025-2.82550.33861390.27642797X-RAY DIFFRACTION99
2.8255-2.97450.33791210.27332843X-RAY DIFFRACTION99
2.9745-3.16080.30831590.26512785X-RAY DIFFRACTION99
3.1608-3.40470.29951880.22632780X-RAY DIFFRACTION99
3.4047-3.74720.24991600.20112831X-RAY DIFFRACTION100
3.7472-4.28920.20191620.16822803X-RAY DIFFRACTION100
4.2892-5.40260.21831580.15222845X-RAY DIFFRACTION100
5.4026-46.530.19971550.14862822X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -23.6246 Å / Origin y: -4.9769 Å / Origin z: 22.2643 Å
111213212223313233
T0.3405 Å2-0.0499 Å2-0.0617 Å2-0.4057 Å2-0.0172 Å2--0.4701 Å2
L0.7614 °2-0.1026 °20.1495 °2-1.1454 °20.1162 °2--8.3192 °2
S-0.0447 Å °0.1651 Å °-0.0184 Å °0.0217 Å °-0.0812 Å °-0.0714 Å °-0.4749 Å °0.1791 Å °0.0823 Å °
Refinement TLS groupSelection details: (chain A and resid 299:716)

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