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

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Basic information

Entry
Database: PDB / ID: 6ngj
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with 6-(3-fluoro-5-(3-(methylamino)prop-1-yn-1-yl)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 / 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 / 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 / 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 / positive regulation of sodium ion transmembrane transport / response to nitric oxide / nitric oxide metabolic process / postsynaptic specialization, intracellular component / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / Ion homeostasis / negative regulation of cytosolic calcium ion concentration / peptidyl-cysteine S-nitrosylation / cadmium ion binding / positive regulation of the force of heart contraction / calyx of Held / negative regulation of potassium ion transport / negative regulation of calcium ion transport / behavioral response to cocaine / negative regulation of serotonin uptake / regulation of neurogenesis / nitric-oxide synthase (NADPH) / response to vitamin E / sodium channel regulator activity / regulation of postsynaptic membrane potential / postsynaptic density, intracellular component / negative regulation of insulin secretion / nitric oxide mediated signal transduction / multicellular organismal response to stress / nitric-oxide synthase activity / xenobiotic catabolic process / NADPH binding / arginine catabolic process / striated muscle contraction / regulation of sodium ion transport / nitric oxide-cGMP-mediated signaling / T-tubule / : / sarcoplasmic reticulum membrane / cellular response to epinephrine stimulus / nitric oxide biosynthetic process / negative regulation of blood pressure / photoreceptor inner segment / response to nutrient levels / response to hormone / secretory granule / response to activity / sarcoplasmic reticulum / positive regulation of long-term synaptic potentiation / muscle contraction / establishment of localization in cell / cell periphery / female pregnancy / phosphoprotein binding / response to lead ion / response to nicotine / potassium ion transport / establishment of protein localization / response to organic cyclic compound / sarcolemma / cellular response to growth factor stimulus / response to peptide hormone / Z disc / cellular response to mechanical stimulus / response to estrogen / vasodilation / calcium ion transport / calcium-dependent protein binding / FMN binding / positive regulation of peptidyl-serine phosphorylation / NADP binding / flavin adenine dinucleotide binding / ATPase binding / response to heat / scaffold protein binding / nuclear membrane / response to ethanol / mitochondrial outer membrane / transmembrane transporter binding / negative regulation of neuron apoptotic process / response to lipopolysaccharide / dendritic spine / postsynaptic density / cytoskeleton / calmodulin binding / response to hypoxia / membrane raft / negative regulation of cell population proliferation / glutamatergic synapse / synapse / dendrite / heme binding / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / enzyme binding
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, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 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, 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 / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
ACETATE ION / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-KLY / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.756 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 1.3Mar 13, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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)100,11911
Polymers97,6252
Non-polymers2,4949
Water7,422412
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9850 Å2
ΔGint-122 kcal/mol
Surface area33980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.346, 112.065, 165.542
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, 421 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-KLY / 6-(2-{3-fluoro-5-[3-(methylamino)prop-1-yn-1-yl]phenyl}ethyl)-4-methylpyridin-2-amine


Mass: 297.370 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H20FN3
#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.: 412 / 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: 50.4 % / 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: SSRL / Beamline: BL9-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Nov 26, 2016 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. obs: 97669 / % possible obs: 99.3 % / Observed criterion σ(I): -3 / Redundancy: 5.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.064 / Rpim(I) all: 0.029 / Rsym value: 0.064 / Net I/σ(I): 10.8
Reflection shellResolution: 1.75→1.8 Å / Redundancy: 5.3 % / Rmerge(I) obs: 3.004 / Mean I/σ(I) obs: 0.6 / Num. unique obs: 4423 / CC1/2: 0.527 / Rpim(I) all: 1.423 / Rsym value: 3.004 / % possible all: 92.6

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.756→39.316 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.09 / Phase error: 29.85
RfactorNum. reflection% reflectionSelection details
Rfree0.2172 9003 5.01 %random
Rwork0.1822 ---
obs0.184 94437 95.7 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.756→39.316 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6677 0 173 412 7262
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087088
X-RAY DIFFRACTIONf_angle_d1.0969644
X-RAY DIFFRACTIONf_dihedral_angle_d15.6952582
X-RAY DIFFRACTIONf_chiral_restr0.04998
X-RAY DIFFRACTIONf_plane_restr0.0051218
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7556-1.77560.47372030.43953874X-RAY DIFFRACTION65
1.7756-1.79650.43822600.4194771X-RAY DIFFRACTION80
1.7965-1.81840.41092560.40754272X-RAY DIFFRACTION73
1.8184-1.84140.43152890.37745119X-RAY DIFFRACTION86
1.8414-1.86560.38993250.35785711X-RAY DIFFRACTION96
1.8656-1.89120.40412860.3445788X-RAY DIFFRACTION98
1.8912-1.91820.37432860.31725841X-RAY DIFFRACTION98
1.9182-1.94680.32863250.2995837X-RAY DIFFRACTION98
1.9468-1.97720.32832990.29375827X-RAY DIFFRACTION99
1.9772-2.00960.33283360.28655952X-RAY DIFFRACTION99
2.0096-2.04430.30432790.26175832X-RAY DIFFRACTION99
2.0443-2.08150.26383060.23945942X-RAY DIFFRACTION99
2.0815-2.12150.28963110.24435861X-RAY DIFFRACTION99
2.1215-2.16480.30052510.23565928X-RAY DIFFRACTION98
2.1648-2.21190.31162680.22725729X-RAY DIFFRACTION96
2.2119-2.26330.24493080.2055918X-RAY DIFFRACTION99
2.2633-2.31990.27083630.20555841X-RAY DIFFRACTION99
2.3199-2.38260.23743240.19325954X-RAY DIFFRACTION99
2.3826-2.45270.2482900.19685856X-RAY DIFFRACTION99
2.4527-2.53190.24642840.20375961X-RAY DIFFRACTION100
2.5319-2.62240.24613440.19135949X-RAY DIFFRACTION100
2.6224-2.72730.25672840.20515890X-RAY DIFFRACTION100
2.7273-2.85140.24562950.19935815X-RAY DIFFRACTION98
2.8514-3.00170.21823160.1835949X-RAY DIFFRACTION100
3.0017-3.18970.22513400.1885893X-RAY DIFFRACTION100
3.1897-3.43580.18793030.17226005X-RAY DIFFRACTION100
3.4358-3.78130.18413130.14935921X-RAY DIFFRACTION100
3.7813-4.32790.16733030.12975863X-RAY DIFFRACTION98
4.3279-5.45040.15973560.12415888X-RAY DIFFRACTION100
5.4504-39.32620.15833000.14715886X-RAY DIFFRACTION99
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)
10.852-0.203-0.65780.92410.19927.178-0.02750.1572-0.0142-0.0094-0.06710.0364-0.0267-0.33540.0610.2744-0.00780.00360.25230.00880.269811.43874.847222.6725
20.767-0.233-0.06181.15310.41883.7338-0.0168-0.030.0696-0.1141-0.0517-0.0310.18820.13120.05590.18060.00930.04230.2220.01760.279212.42234.813360.2687
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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