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- PDB-8fgb: Structure of rat neuronal nitric oxide synthase heme domain in co... -

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Basic information

Entry
Database: PDB / ID: 8fgb
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with 4-(5-(2-(dimethylamino)ethyl)-2,3-difluorophenethyl)-6-methylpyrimidin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / nitric oxide synthase inhibitor / heme enzyme / OXIDOREDUCTASE / OXIDOREDUCTASE-Inhibitor complex / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


Nitric oxide stimulates guanylate cyclase / negative regulation of hepatic stellate cell contraction / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / azurophil granule / negative regulation of vasoconstriction / retrograde trans-synaptic signaling by nitric oxide / Ion homeostasis / positive regulation of sodium ion transmembrane transport ...Nitric oxide stimulates guanylate cyclase / negative regulation of hepatic stellate cell contraction / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / azurophil granule / negative regulation of vasoconstriction / retrograde trans-synaptic signaling by nitric oxide / Ion homeostasis / positive regulation of sodium ion transmembrane transport / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / response to nitric oxide / postsynaptic specialization, intracellular component / nitric oxide metabolic process / negative regulation of cytosolic calcium ion concentration / peptidyl-cysteine S-nitrosylation / postsynaptic density, intracellular component / cadmium ion binding / behavioral response to cocaine / positive regulation of the force of heart contraction / negative regulation of potassium ion transport / calyx of Held / negative regulation of calcium ion transport / negative regulation of serotonin uptake / sodium channel regulator activity / regulation of neurogenesis / striated muscle contraction / negative regulation of insulin secretion / response to vitamin E / nitric-oxide synthase (NADPH) / regulation of postsynaptic membrane potential / multicellular organismal response to stress / xenobiotic catabolic process / nitric-oxide synthase activity / arginine catabolic process / negative regulation of peptidyl-serine phosphorylation / NADPH binding / regulation of sodium ion transport / nitric oxide mediated signal transduction / response to organonitrogen compound / cellular response to epinephrine stimulus / sarcoplasmic reticulum membrane / T-tubule / nitric oxide biosynthetic process / negative regulation of blood pressure / photoreceptor inner segment / response to hormone / response to nutrient levels / response to activity / response to nicotine / sarcoplasmic reticulum / muscle contraction / secretory granule / female pregnancy / positive regulation of long-term synaptic potentiation / cell periphery / establishment of localization in cell / phosphoprotein binding / response to lead ion / sarcolemma / establishment of protein localization / potassium ion transport / response to organic cyclic compound / response to peptide hormone / cellular response to growth factor stimulus / Z disc / cellular response to mechanical stimulus / response to estrogen / vasodilation / calcium-dependent protein binding / calcium ion transport / FMN binding / flavin adenine dinucleotide binding / positive regulation of peptidyl-serine phosphorylation / NADP binding / ATPase binding / response to heat / scaffold protein binding / response to ethanol / nuclear membrane / negative regulation of neuron apoptotic process / mitochondrial outer membrane / transmembrane transporter binding / response to lipopolysaccharide / dendritic spine / postsynaptic density / response to hypoxia / cytoskeleton / calmodulin binding / membrane raft / negative regulation of cell population proliferation / dendrite / synapse / glutamatergic synapse / heme binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II
Similarity search - Function
Nitric-oxide synthase, eukaryote / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain 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 ...Nitric-oxide synthase, eukaryote / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain 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 / Chem-V80 / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.91 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
B: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,16511
Polymers97,6252
Non-polymers2,5409
Water5,549308
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9870 Å2
ΔGint-125 kcal/mol
Surface area33460 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.133, 111.844, 165.007
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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, 317 molecules

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


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN / Tetrahydrobiopterin


Mass: 241.247 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#4: Chemical ChemComp-V80 / 4-(2-{5-[2-(dimethylamino)ethyl]-2,3-difluorophenyl}ethyl)-6-methylpyrimidin-2-amine


Mass: 320.380 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H22F2N4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ACT / ACETATE ION / Acetate


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 / Water


Mass: 18.015 Da / Num. of mol.: 308 / 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: 6.8
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: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 19, 2020 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.91→39.2219 Å / Num. obs: 75859 / % possible obs: 100 % / Redundancy: 13.6 % / Biso Wilson estimate: 35.5 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.245 / Rpim(I) all: 0.068 / Rrim(I) all: 0.254 / Net I/σ(I): 7.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.91-1.957.44.0243283144220.4161.5694.3250.7100
9.55-39.2113.70.08397697110.9950.0230.08628.198.8

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Processing

Software
NameVersionClassification
Aimless0.2.8data scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1OM4

1om4


Resolution: 1.91→39.2219 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 35.69 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.241 7095 4.98 %random
Rwork0.2015 135395 --
obs0.2035 74946 98.55 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 152.51 Å2 / Biso mean: 63.922 Å2 / Biso min: 26.84 Å2
Refinement stepCycle: final / Resolution: 1.91→39.2219 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6726 0 175 308 7209
Biso mean--55.13 59.75 -
Num. residues----826
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087127
X-RAY DIFFRACTIONf_angle_d0.9929696
X-RAY DIFFRACTIONf_chiral_restr0.0511005
X-RAY DIFFRACTIONf_plane_restr0.0061223
X-RAY DIFFRACTIONf_dihedral_angle_d17.7034154
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.91-1.93170.50842140.52694194440891
1.9317-1.95440.51112260.44674306453295
1.9544-1.97830.482540.44394265451994
1.9783-2.00330.44912470.40334323457094
2.0033-2.02970.37082020.35854542474499
2.0297-2.05750.35212330.32244471470497
2.0575-2.08690.33792580.31444478473698
2.0869-2.1180.42552280.30494521474999
2.118-2.15110.40581800.31194592477299
2.1511-2.18640.3922110.31214618482999
2.1864-2.22410.39592300.30654444467499
2.2241-2.26450.43552360.36634584482099
2.2645-2.30810.36692940.29714415470999
2.3081-2.35520.33032570.25654562481999
2.3552-2.40640.27452170.23514555477299
2.4064-2.46230.28142330.232146074840100
2.4623-2.52390.31822180.228245534771100
2.5239-2.59210.26282520.23074539479199
2.5921-2.66840.26142150.23734573478899
2.6684-2.75450.27392450.237646044849100
2.7545-2.85290.25072290.212245424771100
2.8529-2.96710.25262340.211745334767100
2.9671-3.10210.22952720.21845964868100
3.1021-3.26560.27412410.212745874828100
3.2656-3.47010.21322180.185345904808100
3.4701-3.73780.22082500.166745604810100
3.7378-4.11360.17452470.143545544801100
4.1136-4.7080.16722470.131745804827100
4.708-5.92820.19752860.140245224808100
5.9282-39.22190.16832210.151745854806100
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)
10.8805-0.0276-0.02781.0770.1325.1325-0.01690.09010.04830.0466-0.08690.0662-0.124-0.19520.06570.31710.03790.01690.3055-0.02390.323711.29254.786722.7326
20.9433-0.3308-0.05971.11460.52363.05820.00860.00240.0729-0.1112-0.0763-0.01820.14270.0660.0630.2578-0.02540.03550.2920.02320.342812.57595.137460.2896
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1(chain A and resid 299:716)A299 - 716
2X-RAY DIFFRACTION2(chain B and resid 299:718)B299 - 718

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