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

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Basic information

Entry
Database: PDB / ID: 8fgc
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with 6-(5-(2-aminoethyl)-2,3-difluorophenethyl)-4-methylpyridin-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


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-XVZ / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.779 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)100,10711
Polymers97,6252
Non-polymers2,4829
Water7,728429
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9890 Å2
ΔGint-127 kcal/mol
Surface area33420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.098, 111.356, 164.401
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, 438 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
#4: Chemical ChemComp-XVZ / 6-{2-[5-(2-aminoethyl)-2,3-difluorophenyl]ethyl}-4-methylpyridin-2-amine


Mass: 291.339 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H19F2N3 / 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.: 429 / 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: Nov 3, 2021 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.779→39.06 Å / Num. obs: 92683 / % possible obs: 99.8 % / Redundancy: 10.8 % / CC1/2: 0.997 / Rmerge(I) obs: 0.171 / Rpim(I) all: 0.053 / Rrim(I) all: 0.18 / Net I/σ(I): 8.6
Reflection shellResolution: 1.78→1.81 Å / Redundancy: 5.6 % / Rmerge(I) obs: 6.007 / Num. unique obs: 4368 / CC1/2: 0.316 / Rpim(I) all: 2.733 / Rrim(I) all: 6.617 / % possible all: 96.2

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Processing

Software
NameVersionClassification
Aimless0.2.8data scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1OM4

1om4


Resolution: 1.779→39.056 Å / SU ML: 0.25 / Cross valid method: THROUGHOUT / σ(F): 0.01 / Phase error: 34.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2263 8773 5 %random
Rwork0.1897 ---
obs0.1916 91895 98.86 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.779→39.056 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6683 0 170 429 7282
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077079
X-RAY DIFFRACTIONf_angle_d0.9799631
X-RAY DIFFRACTIONf_dihedral_angle_d18.2364125
X-RAY DIFFRACTIONf_chiral_restr0.049997
X-RAY DIFFRACTIONf_plane_restr0.0061215
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.779-1.79880.43912840.36994866X-RAY DIFFRACTION86
1.7988-1.820.44273200.3535352X-RAY DIFFRACTION97
1.82-1.84220.42082930.35325528X-RAY DIFFRACTION98
1.8422-1.86550.37473180.34425622X-RAY DIFFRACTION99
1.8655-1.89010.44742460.33345630X-RAY DIFFRACTION99
1.8901-1.91590.38032700.32535591X-RAY DIFFRACTION99
1.9159-1.94330.3953190.32875480X-RAY DIFFRACTION99
1.9433-1.97230.39923030.3185551X-RAY DIFFRACTION99
1.9723-2.00310.37083070.31625622X-RAY DIFFRACTION99
2.0031-2.0360.34692800.30835506X-RAY DIFFRACTION99
2.036-2.07110.34422810.29755624X-RAY DIFFRACTION99
2.0711-2.10870.35072920.28185502X-RAY DIFFRACTION99
2.1087-2.14930.30432430.25615639X-RAY DIFFRACTION99
2.1493-2.19320.32432640.25775627X-RAY DIFFRACTION99
2.1932-2.24090.33462860.24325590X-RAY DIFFRACTION99
2.2409-2.2930.2633400.2475509X-RAY DIFFRACTION100
2.293-2.35030.29153160.23425527X-RAY DIFFRACTION99
2.3503-2.41380.30392870.2275607X-RAY DIFFRACTION99
2.4138-2.48490.34382680.23125682X-RAY DIFFRACTION100
2.4849-2.56510.27942860.2075544X-RAY DIFFRACTION99
2.5651-2.65670.24782730.20615594X-RAY DIFFRACTION99
2.6567-2.76310.25242930.21065631X-RAY DIFFRACTION100
2.7631-2.88880.24872850.20155619X-RAY DIFFRACTION100
2.8888-3.0410.21943140.20045594X-RAY DIFFRACTION100
3.041-3.23150.28813130.20835601X-RAY DIFFRACTION100
3.2315-3.48080.21442590.18015673X-RAY DIFFRACTION100
3.4808-3.83080.18123270.1495563X-RAY DIFFRACTION100
3.8308-4.38450.14032740.13245650X-RAY DIFFRACTION100
4.3845-5.52160.15973440.12815555X-RAY DIFFRACTION100
5.5216-39.0560.16312880.15525624X-RAY DIFFRACTION100
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)
10.7623-0.1041-0.58250.9884-0.29526.6128-0.02950.1492-0.0048-0.0027-0.07320.0427-0.0271-0.38830.08110.3086-0.00790.00040.3523-0.0140.339411.3614.86822.429
20.796-0.147-0.22280.9180.35953.2399-0.0074-0.01120.0422-0.1097-0.0657-0.01360.10210.12230.06330.25880.00740.02840.2830.02340.323812.274.78659.841
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 300:718 )B300 - 718

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