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- PDB-9cvn: Structure of rat neuronal nitric oxide synthase bound with 6-(2,3... -

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Basic information

Entry
Database: PDB / ID: 9cvn
TitleStructure of rat neuronal nitric oxide synthase bound with 6-(2,3-difluoro-5-((methylamino)methyl)phenyl)-4-methylpyridin-2-amine dihydrochloride
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/INHIBITOR / nitric oxide synthase inhibitor binding / 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 / negative regulation of vasoconstriction / peptidyl-cysteine S-nitrosylation ...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 / negative regulation of vasoconstriction / peptidyl-cysteine S-nitrosylation / postsynaptic specialization, intracellular component / 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 / cadmium ion binding / nitric oxide metabolic process / 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 / regulation of postsynaptic membrane potential / 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 / striated muscle contraction / NADPH binding / regulation of sodium ion transport / nitric oxide-cGMP-mediated signaling / negative regulation of blood pressure / response to hormone / photoreceptor inner segment / sarcoplasmic reticulum membrane / T-tubule / cellular response to epinephrine stimulus / 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 nutrient levels / response to lead ion / 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-dependent protein binding / calcium ion transport / 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: 1.85 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

Downloads & links

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Assembly

Deposited unit
A: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,9726
Polymers48,7261
Non-polymers1,2455
Water54030
1
A: Nitric oxide synthase, brain
hetero molecules

A: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)99,94412
Polymers97,4532
Non-polymers2,49110
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_455-x-1,y,-z+1/21
Buried area9820 Å2
ΔGint-143 kcal/mol
Surface area33990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.010, 113.845, 164.367
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, 35 molecules

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


Mass: 616.487 Da / Num. of mol.: 1 / Source method: isolated from a natural source / 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-A1A0B / (6M)-6-{2,3-difluoro-5-[(methylamino)methyl]phenyl}-4-methylpyridin-2-amine


Mass: 263.286 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H15F2N3 / 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.: 30 / 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: SSRL / Beamline: BL12-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 13, 2022 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.85→39.48 Å / Num. obs: 39793 / % possible obs: 99.5 % / Redundancy: 6.7 % / CC1/2: 0.996 / Rmerge(I) obs: 0.09 / Rpim(I) all: 0.032 / Rrim(I) all: 0.096 / Net I/σ(I): 6.5 / Num. measured all: 268272
Reflection shellResolution: 1.85→1.89 Å / % possible obs: 93.7 % / Redundancy: 5.2 % / Rmerge(I) obs: 6.526 / Num. measured all: 11908 / Num. unique obs: 2297 / CC1/2: 0.375 / Rpim(I) all: 3.087 / Rrim(I) all: 7.248 / Net I/σ(I) obs: 0.1

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
Aimlessdata scaling
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.85→39.48 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 0.04 / Phase error: 44.74 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2564 3635 5.1 %random
Rwork0.216 ---
obs0.2181 37605 93.74 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.85→39.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3334 0 84 30 3448
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0083525
X-RAY DIFFRACTIONf_angle_d1.0444796
X-RAY DIFFRACTIONf_dihedral_angle_d18.9382047
X-RAY DIFFRACTIONf_chiral_restr0.05497
X-RAY DIFFRACTIONf_plane_restr0.006605
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.87270.52851170.48162010X-RAY DIFFRACTION72
1.8727-1.89830.58521120.47992179X-RAY DIFFRACTION79
1.8983-1.92550.46841070.45882279X-RAY DIFFRACTION82
1.9255-1.95420.4891280.45032346X-RAY DIFFRACTION83
1.9542-1.98470.43771640.45072380X-RAY DIFFRACTION88
1.9847-2.01730.44811210.41322497X-RAY DIFFRACTION90
2.0173-2.0520.53831280.38932580X-RAY DIFFRACTION92
2.052-2.08940.407930.37292607X-RAY DIFFRACTION95
2.0894-2.12950.40141910.37572675X-RAY DIFFRACTION96
2.1295-2.1730.45611480.35022618X-RAY DIFFRACTION96
2.173-2.22030.36121270.33762722X-RAY DIFFRACTION95
2.2203-2.27190.40051720.30562588X-RAY DIFFRACTION96
2.2719-2.32870.35161330.29452667X-RAY DIFFRACTION96
2.3287-2.39170.38191480.29852653X-RAY DIFFRACTION95
2.3917-2.4620.3531320.29762696X-RAY DIFFRACTION97
2.462-2.54150.39511250.2772689X-RAY DIFFRACTION97
2.5415-2.63230.29511250.26752726X-RAY DIFFRACTION97
2.6323-2.73770.34421460.25892762X-RAY DIFFRACTION98
2.7377-2.86220.27441370.2552714X-RAY DIFFRACTION98
2.8622-3.01310.29591190.26522763X-RAY DIFFRACTION99
3.0131-3.20180.31641580.25982746X-RAY DIFFRACTION99
3.2018-3.44890.26151800.22382752X-RAY DIFFRACTION99
3.4489-3.79570.19611510.19662745X-RAY DIFFRACTION100
3.7957-4.34430.22331610.1672744X-RAY DIFFRACTION100
4.3443-5.47110.18271620.14732776X-RAY DIFFRACTION100
5.4711-39.480.18431500.14952768X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -23.6598 Å / Origin y: -4.8496 Å / Origin z: 22.2991 Å
111213212223313233
T0.4408 Å2-0.0422 Å2-0.0649 Å2-0.4644 Å2-0.0012 Å2--0.5314 Å2
L0.8629 °2-0.0069 °20.5308 °2-1.2247 °20.0285 °2--8.7657 °2
S-0.0486 Å °0.1505 Å °0.0055 Å °-0.0068 Å °-0.0701 Å °-0.0579 Å °-0.9214 Å °0.2978 Å °0.069 Å °
Refinement TLS groupSelection details: (chain A and resid 299:716)

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