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- PDB-8fge: Structure of rat neuronal nitric oxide synthase R349A mutant heme... -

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Basic information

Entry
Database: PDB / ID: 8fge
TitleStructure of rat neuronal nitric oxide synthase R349A mutant heme domain in complex with 4-(difluoromethyl)-6-(5-(2-(dimethylamino)ethyl)-2,3-difluorophenethyl)pyridin-2-amine dihydrochloride
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHBITOR / nitric oxide synthase inhibitor / heme enzyme / OXIDOREDUCTASE / OXIDOREDUCTASE-Inhibitor complex / OXIDOREDUCTASE-OXIDOREDUCTASE INHBITOR complex
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 / negative regulation of iron ion transmembrane transport / response to vitamin B3 / postsynaptic specialization, intracellular component / ROS and RNS production in phagocytes / azurophil granule / synaptic signaling by nitric oxide / Ion homeostasis ...negative regulation of hepatic stellate cell contraction / Nitric oxide stimulates guanylate cyclase / positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / negative regulation of iron ion transmembrane transport / response to vitamin B3 / postsynaptic specialization, intracellular component / ROS and RNS production in phagocytes / azurophil granule / synaptic signaling by nitric oxide / Ion homeostasis / negative regulation of vasoconstriction / response to nitric oxide / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of cytosolic calcium ion concentration / response to vitamin E / positive regulation of sodium ion transmembrane transport / peptidyl-cysteine S-nitrosylase activity / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of calcium ion transport / negative regulation of potassium ion transport / regulation of postsynaptic membrane potential / nitric oxide mediated signal transduction / nitric-oxide synthase (NADPH) / sodium channel regulator activity / regulation of neurogenesis / negative regulation of serotonin uptake / nitric-oxide synthase activity / multicellular organismal response to stress / xenobiotic catabolic process / L-arginine catabolic process / postsynaptic density, intracellular component / NADPH binding / striated muscle contraction / nitric oxide-cGMP-mediated signaling / regulation of sodium ion transport / negative regulation of blood pressure / behavioral response to cocaine / response to hormone / nitric oxide metabolic process / nitric oxide biosynthetic process / photoreceptor inner segment / cellular response to epinephrine stimulus / T-tubule / sarcoplasmic reticulum membrane / secretory granule / calyx of Held / sarcoplasmic reticulum / positive regulation of long-term synaptic potentiation / response to activity / cell periphery / response to nicotine / response to nutrient levels / phosphoprotein binding / establishment of protein localization / establishment of localization in cell / cellular response to mechanical stimulus / female pregnancy / negative regulation of insulin secretion / response to peptide hormone / sarcolemma / caveola / cellular response to growth factor stimulus / potassium ion transport / response to lead ion / response to estrogen / vasodilation / Z disc / calcium-dependent protein binding / calcium ion transport / FMN binding / NADP binding / flavin adenine dinucleotide binding / positive regulation of neuron apoptotic process / response to heat / ATPase binding / scaffold protein binding / response to ethanol / nuclear membrane / response to lipopolysaccharide / dendritic spine / negative regulation of neuron apoptotic process / RNA polymerase II-specific DNA-binding transcription factor binding / transmembrane transporter binding / mitochondrial outer membrane / cytoskeleton / calmodulin binding / response to hypoxia / postsynaptic density / membrane raft / negative regulation of cell population proliferation / heme binding / synapse / 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
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 / PDZ 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 / 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 / Chem-XVA / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.89 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)GM57353 United States
CitationJournal: J.Med.Chem. / Year: 2023
Title: Potent, Selective, and Membrane Permeable 2-Amino-4-Substituted Pyridine-Based Neuronal Nitric Oxide Synthase Inhibitors.
Authors: Vasu, D. / Do, H.T. / Li, H. / Hardy, C.D. / Awasthi, A. / Poulos, T.L. / Silverman, R.B.
History
DepositionDec 12, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 11, 2023Provider: 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)50,0646
Polymers48,7261
Non-polymers1,3385
Water1,49583
1
A: Nitric oxide synthase, brain
hetero molecules

A: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,12812
Polymers97,4532
Non-polymers2,67510
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_455-x-1,y,-z+1/21
Buried area10120 Å2
ΔGint-213 kcal/mol
Surface area33080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)48.953, 113.846, 163.630
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-955-

HOH

21A-962-

HOH

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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: pCWori / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P29476, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 88 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
#4: Chemical ChemComp-XVA / 4-(difluoromethyl)-6-(2-{5-[2-(dimethylamino)ethyl]-2,3-difluorophenyl}ethyl)pyridin-2-amine


Mass: 355.373 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H21F4N3 / 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.: 83 / 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: 2.34 Å3/Da / Density % sol: 47.33 %
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: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jun 10, 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: 1.88→46.73 Å / Num. obs: 37540 / % possible obs: 100 % / Redundancy: 11.9 % / Biso Wilson estimate: 37.28 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.128 / Rpim(I) all: 0.039 / Rrim(I) all: 0.134 / Net I/σ(I): 10
Reflection shellResolution: 1.88→1.92 Å / Redundancy: 12.1 % / Rmerge(I) obs: 6.356 / Num. unique obs: 2347 / CC1/2: 0.641 / Rpim(I) all: 1.896 / Rrim(I) all: 6.637 / % possible all: 99.3

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIXJan 10, 2022refinement
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 7TS9

7ts9


Resolution: 1.89→46.726 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 0.05 / Phase error: 37.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2482 3498 5.08 %random
Rwork0.2088 ---
obs0.2109 36297 97.42 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.89→46.726 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3341 0 90 83 3514
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073538
X-RAY DIFFRACTIONf_angle_d0.9794813
X-RAY DIFFRACTIONf_dihedral_angle_d19.122058
X-RAY DIFFRACTIONf_chiral_restr0.05500
X-RAY DIFFRACTIONf_plane_restr0.005606
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8901-1.9160.41531230.40032304X-RAY DIFFRACTION87
1.916-1.94330.4211210.3732406X-RAY DIFFRACTION88
1.9433-1.97230.3991520.36462358X-RAY DIFFRACTION90
1.9723-2.00320.40581390.34722526X-RAY DIFFRACTION93
2.0032-2.0360.35281240.32542510X-RAY DIFFRACTION94
2.036-2.07110.34691110.33782669X-RAY DIFFRACTION98
2.0711-2.10880.33421520.30962626X-RAY DIFFRACTION98
2.1088-2.14930.39911550.30112636X-RAY DIFFRACTION99
2.1493-2.19320.33821370.28132630X-RAY DIFFRACTION98
2.1932-2.24090.3491560.28162676X-RAY DIFFRACTION99
2.2409-2.2930.30571410.26862658X-RAY DIFFRACTION99
2.293-2.35040.38881290.26652617X-RAY DIFFRACTION99
2.3504-2.41390.33861490.26342700X-RAY DIFFRACTION99
2.4139-2.48490.3081260.2652645X-RAY DIFFRACTION99
2.4849-2.56510.25951280.23692696X-RAY DIFFRACTION99
2.5651-2.65680.33021400.24762656X-RAY DIFFRACTION99
2.6568-2.76320.30081260.24192671X-RAY DIFFRACTION100
2.7632-2.88890.26221340.24272710X-RAY DIFFRACTION100
2.8889-3.04120.3341230.25182674X-RAY DIFFRACTION100
3.0412-3.23170.24671630.24792684X-RAY DIFFRACTION100
3.2317-3.48110.26621660.20852673X-RAY DIFFRACTION100
3.4811-3.83130.19761420.18132663X-RAY DIFFRACTION100
3.8313-4.38530.18231560.16292689X-RAY DIFFRACTION100
4.3853-5.52370.22671650.14852650X-RAY DIFFRACTION100
5.5237-46.7260.17831400.15432689X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -23.7023 Å / Origin y: -4.8277 Å / Origin z: 22.276 Å
111213212223313233
T0.2253 Å2-0.0384 Å2-0.057 Å2-0.2994 Å2-0.0259 Å2--0.3944 Å2
L0.851 °2-0.152 °2-0.1617 °2-1.3485 °20.1106 °2--8.8522 °2
S-0.0583 Å °0.1585 Å °-0.0535 Å °-0.0227 Å °-0.1148 Å °-0.0282 Å °-0.3723 Å °0.1006 Å °0.1132 Å °
Refinement TLS groupSelection details: (chain A and resid 299:716)

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