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

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Basic information

Entry
Database: PDB / ID: 6ngy
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with (R)-6-(2,3-difluoro-5-(2-(1-methylpyrrolidin-2-yl)ethyl)phenethyl)-4-methylpyridin-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 / positive regulation of sodium ion transmembrane transport / negative regulation of vasoconstriction ...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 / positive regulation of sodium ion transmembrane transport / negative regulation of vasoconstriction / 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 / calyx of Held / regulation of neurogenesis / negative regulation of serotonin uptake / nitric-oxide synthase (NADPH) / regulation of postsynaptic membrane potential / response to vitamin E / sodium channel regulator activity / nitric oxide mediated signal transduction / postsynaptic density, intracellular component / nitric-oxide synthase activity / negative regulation of insulin secretion / xenobiotic catabolic process / multicellular organismal response to stress / arginine catabolic process / NADPH binding / striated muscle contraction / regulation of sodium ion transport / nitric oxide-cGMP-mediated signaling / nitric oxide biosynthetic process / T-tubule / 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 / cell periphery / response to activity / female pregnancy / establishment of localization in cell / phosphoprotein binding / response to nicotine / response to lead ion / establishment of protein localization / potassium ion transport / caveola / sarcolemma / response to organic cyclic compound / cellular response to growth factor stimulus / response to peptide hormone / Z disc / response to estrogen / cellular response to mechanical stimulus / 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 / transmembrane transporter binding / mitochondrial outer membrane / response to lipopolysaccharide / dendritic spine / postsynaptic density / cytoskeleton / calmodulin binding / response to hypoxia / membrane raft / negative regulation of cell population proliferation / glutamatergic synapse / heme binding / dendrite / 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-KN4 / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.928 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: 2019
Title: Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold.
Authors: Do, H.T. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionDec 21, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2019Group: Data collection / 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 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id

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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)100,42713
Polymers97,6252
Non-polymers2,80211
Water5,549308
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10370 Å2
ΔGint-125 kcal/mol
Surface area32930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.843, 111.110, 164.285
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 , 7 types, 319 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-KN4 / 6-[2-(2,3-difluoro-5-{2-[(2R)-1-methylpyrrolidin-2-yl]ethyl}phenyl)ethyl]-4-methylpyridin-2-amine


Mass: 359.456 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27F2N3
#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: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 308 / Source method: isolated from a natural source / Formula: H2O

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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: 50.44 % / 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: SSRL / Beamline: BL12-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Nov 20, 2017
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.928→60 Å / Num. obs: 72182 / % possible obs: 99.4 % / Observed criterion σ(I): -3 / Redundancy: 11.4 % / CC1/2: 0.998 / Rmerge(I) obs: 0.176 / Rpim(I) all: 0.054 / Rsym value: 0.176 / Net I/σ(I): 9.7
Reflection shellResolution: 1.93→1.99 Å / Redundancy: 5.9 % / Rmerge(I) obs: 5.789 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 3988 / CC1/2: 0.313 / Rpim(I) all: 2.478 / Rsym value: 5.789 / % possible all: 90.7

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Processing

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

1om4


Resolution: 1.928→39 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 0.05 / Phase error: 34.81
RfactorNum. reflection% reflectionSelection details
Rfree0.2303 6772 4.97 %random
Rwork0.1874 ---
obs0.1895 71610 98.64 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.928→39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6708 0 193 308 7209
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077125
X-RAY DIFFRACTIONf_angle_d0.9839691
X-RAY DIFFRACTIONf_dihedral_angle_d17.3114153
X-RAY DIFFRACTIONf_chiral_restr0.051003
X-RAY DIFFRACTIONf_plane_restr0.0061220
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9283-1.95020.44581790.3753440X-RAY DIFFRACTION78
1.9502-1.97320.45712560.36834145X-RAY DIFFRACTION96
1.9732-1.99720.40652150.34754296X-RAY DIFFRACTION97
1.9972-2.02250.38212080.32154299X-RAY DIFFRACTION99
2.0225-2.04910.33282190.31054338X-RAY DIFFRACTION99
2.0491-2.07720.38022470.30954377X-RAY DIFFRACTION99
2.0772-2.10690.38322100.31574330X-RAY DIFFRACTION99
2.1069-2.13830.38121760.31024358X-RAY DIFFRACTION99
2.1383-2.17170.4142000.29344421X-RAY DIFFRACTION99
2.1717-2.20730.3742250.28454272X-RAY DIFFRACTION99
2.2073-2.24540.3422230.28164369X-RAY DIFFRACTION99
2.2454-2.28620.31352890.26464308X-RAY DIFFRACTION100
2.2862-2.33020.30552450.25534348X-RAY DIFFRACTION100
2.3302-2.37770.30031940.2464390X-RAY DIFFRACTION100
2.3777-2.42940.33882320.23794311X-RAY DIFFRACTION99
2.4294-2.48590.35472270.25674411X-RAY DIFFRACTION100
2.4859-2.54810.29252210.23744356X-RAY DIFFRACTION100
2.5481-2.6170.28042320.23134350X-RAY DIFFRACTION99
2.617-2.69390.30462080.22644379X-RAY DIFFRACTION100
2.6939-2.78090.24812090.2214378X-RAY DIFFRACTION100
2.7809-2.88020.25782370.2084370X-RAY DIFFRACTION100
2.8802-2.99550.25162430.20594348X-RAY DIFFRACTION100
2.9955-3.13180.24362520.21594355X-RAY DIFFRACTION100
3.1318-3.29680.26571960.19234420X-RAY DIFFRACTION100
3.2968-3.50330.1782280.16964367X-RAY DIFFRACTION100
3.5033-3.77350.1982560.14774338X-RAY DIFFRACTION100
3.7735-4.15290.19542220.13434365X-RAY DIFFRACTION100
4.1529-4.75290.14932510.12574403X-RAY DIFFRACTION100
4.7529-5.98470.19892580.1384318X-RAY DIFFRACTION100
5.9847-39.00780.15542140.14754398X-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)
11.005-0.2433-0.40361.5129-0.29647.5394-0.05840.1087-0.01820.0779-0.0770.079-0.0491-0.39140.10280.26540.00880.0070.305-0.01360.318811.32694.771922.5551
21.0327-0.1754-0.04441.30340.62993.75120.0007-0.01060.0908-0.1522-0.0719-0.04630.06680.16870.06020.2208-0.00340.04140.26830.0330.317912.31925.014859.8926
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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