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- PDB-6pn2: Structure of rat neuronal nitric oxide synthase heme domain in co... -

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Basic information

Entry
Database: PDB / ID: 6pn2
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with 7-(3-(Aminomethyl)-4-isopropoxyphenyl)-4-methylquinolin-2-amine
ComponentsNitric oxide synthase, brain
Keywordsoxidoreductase/oxidoreductase inhibitor / nitric oxide synthase inhibitor complex heme enzyme / OXIDOREDUCTASE / oxidoreductase-oxidoreductase inhibitor complex
Function / homology
Function and homology information


Nitric oxide stimulates guanylate cyclase / negative regulation of hepatic stellate cell contraction / positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / retrograde trans-synaptic signaling by nitric oxide / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / azurophil granule / negative regulation of vasoconstriction / positive regulation of sodium ion transmembrane transport ...Nitric oxide stimulates guanylate cyclase / negative regulation of hepatic stellate cell contraction / positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / retrograde trans-synaptic signaling by nitric oxide / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / azurophil granule / negative regulation of vasoconstriction / positive regulation of sodium ion transmembrane transport / postsynaptic specialization, intracellular component / nitric oxide metabolic process / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / response to nitric oxide / Ion homeostasis / negative regulation of cytosolic calcium ion concentration / peptidyl-cysteine S-nitrosylation / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of potassium ion transport / negative regulation of calcium ion transport / behavioral response to cocaine / regulation of postsynaptic membrane potential / calyx of Held / regulation of neurogenesis / postsynaptic density, intracellular component / negative regulation of serotonin uptake / nitric-oxide synthase (NADPH) / multicellular organismal response to stress / response to vitamin E / sodium channel regulator activity / nitric oxide mediated signal transduction / negative regulation of insulin secretion / nitric-oxide synthase activity / xenobiotic catabolic process / arginine catabolic process / NADPH binding / striated muscle contraction / regulation of sodium ion transport / nitric oxide-cGMP-mediated signaling / T-tubule / nitric oxide biosynthetic process / cellular response to epinephrine stimulus / sarcoplasmic reticulum membrane / negative regulation of blood pressure / photoreceptor inner segment / response to hormone / response to nutrient levels / secretory granule / sarcoplasmic reticulum / positive regulation of long-term synaptic potentiation / establishment of localization in cell / response to activity / cell periphery / female pregnancy / response to nicotine / phosphoprotein binding / response to lead ion / establishment of protein localization / potassium ion transport / caveola / cellular response to growth factor stimulus / response to organic cyclic compound / sarcolemma / Z disc / response to peptide hormone / cellular response to mechanical stimulus / response to estrogen / vasodilation / calcium-dependent protein binding / calcium ion transport / FMN binding / positive regulation of peptidyl-serine phosphorylation / flavin adenine dinucleotide binding / NADP binding / ATPase binding / response to heat / scaffold protein binding / nuclear membrane / response to ethanol / negative regulation of neuron apoptotic process / mitochondrial outer membrane / transmembrane transporter binding / response to lipopolysaccharide / dendritic spine / postsynaptic density / cytoskeleton / response to hypoxia / calmodulin binding / membrane raft / negative regulation of cell population proliferation / glutamatergic synapse / dendrite / heme binding / synapse / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / enzyme binding / positive regulation of transcription by RNA polymerase II
Similarity search - Function
Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / Nitric-oxide synthase, eukaryote / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain superfamily / Nitric oxide synthase, domain 2 superfamily ...Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / 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 / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
ACETATE ION / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-OSD / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.877 Å
AuthorsLi, H. / Poulos, T.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)GM57353 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.
Authors: Cinelli, M.A. / Reidl, C.T. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionJul 2, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1May 27, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)100,16711
Polymers97,6252
Non-polymers2,5429
Water6,269348
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9840 Å2
ΔGint-125 kcal/mol
Surface area33040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.760, 111.545, 164.485
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) / Strain (production host): BL21(DE3) / References: UniProt: P29476, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 357 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 / Comment: neurotransmitter*YM
#4: Chemical ChemComp-OSD / 7-{3-(aminomethyl)-4-[(propan-2-yl)oxy]phenyl}-4-methylquinolin-2-amine


Mass: 321.416 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H23N3O / 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.: 348 / 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: 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: 8.2.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 4, 2017 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.877→70 Å / Num. obs: 78406 / % possible obs: 99.5 % / Observed criterion σ(I): -3 / Redundancy: 10.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.22 / Rpim(I) all: 0.066 / Rsym value: 0.22 / Net I/σ(I): 7.5
Reflection shellResolution: 1.88→1.93 Å / Redundancy: 5.6 % / Rmerge(I) obs: 3.571 / Mean I/σ(I) obs: 0.5 / Num. unique obs: 4161 / CC1/2: 0.337 / Rpim(I) all: 2.484 / Rsym value: 3.571 / % possible all: 92.8

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Processing

Software
NameVersionClassification
PHENIX(1.11.1-2575_1496: ???)refinement
MOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1OM4

1om4


Resolution: 1.877→66.195 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 33.75
RfactorNum. reflection% reflectionSelection details
Rfree0.2373 7372 4.95 %random
Rwork0.1982 ---
obs0.2001 78072 99.02 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.877→66.195 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6697 0 177 348 7222
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077096
X-RAY DIFFRACTIONf_angle_d0.9179656
X-RAY DIFFRACTIONf_dihedral_angle_d17.2674122
X-RAY DIFFRACTIONf_chiral_restr0.05999
X-RAY DIFFRACTIONf_plane_restr0.0051217
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.877-1.89840.38821880.32434113X-RAY DIFFRACTION85
1.8984-1.92070.39282280.34854707X-RAY DIFFRACTION97
1.9207-1.94410.40392530.35364637X-RAY DIFFRACTION99
1.9441-1.96870.42062780.33074730X-RAY DIFFRACTION100
1.9687-1.99460.37182630.32534766X-RAY DIFFRACTION99
1.9946-2.0220.39822140.32154694X-RAY DIFFRACTION99
2.022-2.05090.34692510.30414785X-RAY DIFFRACTION99
2.0509-2.08150.36062500.31614751X-RAY DIFFRACTION99
2.0815-2.1140.40872250.31724700X-RAY DIFFRACTION100
2.114-2.14870.35782050.29874803X-RAY DIFFRACTION99
2.1487-2.18570.39362270.2944751X-RAY DIFFRACTION100
2.1857-2.22550.38962390.2824741X-RAY DIFFRACTION100
2.2255-2.26830.33652630.28164736X-RAY DIFFRACTION100
2.2683-2.31460.34122880.25984716X-RAY DIFFRACTION100
2.3146-2.36490.28172600.24274783X-RAY DIFFRACTION99
2.3649-2.41990.31332500.23494699X-RAY DIFFRACTION100
2.4199-2.48040.30462250.23914779X-RAY DIFFRACTION100
2.4804-2.54750.30252400.22794740X-RAY DIFFRACTION100
2.5475-2.62250.29632570.21924710X-RAY DIFFRACTION99
2.6225-2.70710.28252270.22694778X-RAY DIFFRACTION100
2.7071-2.80390.25762310.21524730X-RAY DIFFRACTION100
2.8039-2.91610.24782570.19994745X-RAY DIFFRACTION100
2.9161-3.04880.21972670.19654758X-RAY DIFFRACTION100
3.0488-3.20960.22492850.18884706X-RAY DIFFRACTION100
3.2096-3.41070.18592240.16914770X-RAY DIFFRACTION100
3.4107-3.6740.18182450.164771X-RAY DIFFRACTION100
3.674-4.04370.1852410.14714733X-RAY DIFFRACTION100
4.0437-4.62870.17872700.13844753X-RAY DIFFRACTION100
4.6287-5.83110.18872900.14384704X-RAY DIFFRACTION100
5.8311-66.23640.16612310.16894771X-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)
10.6829-0.1832-0.27591.1816-0.00896.6429-0.03030.0952-0.0092-0.0194-0.13180.0758-0.1451-0.29920.09290.2770.0053-0.00310.2869-0.01130.300911.29474.610622.7435
20.8154-0.3127-0.10591.12830.50643.26320.0023-0.01550.0656-0.0686-0.0775-0.03140.06240.13080.0520.213-0.01080.04570.27040.02770.303112.47914.95660.0997
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 299:716)
2X-RAY DIFFRACTION2(chain B and resid 299:718)

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