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- PDB-6nh0: Structure of rat neuronal nitric oxide synthase heme domain in co... -

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Basic information

Entry
Database: PDB / ID: 6nh0
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with (S)-6-(2,3-difluoro-5-(2-(4-methylmorpholin-3-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 / 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-KND / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.898 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)100,45913
Polymers97,6252
Non-polymers2,83411
Water7,728429
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10400 Å2
ΔGint-125 kcal/mol
Surface area33290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.935, 111.275, 164.505
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, 440 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-KND / 6-[2-(2,3-difluoro-5-{2-[(3S)-4-methylmorpholin-3-yl]ethyl}phenyl)ethyl]-4-methylpyridin-2-amine


Mass: 375.455 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H27F2N3O
#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.: 429 / 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, hanging 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: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 4, 2018
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.898→60 Å / Num. obs: 75837 / % possible obs: 99.5 % / Observed criterion σ(I): -3 / Redundancy: 9.3 % / CC1/2: 0.996 / Rmerge(I) obs: 0.159 / Rpim(I) all: 0.055 / Rsym value: 0.159 / Net I/σ(I): 53.5
Reflection shellResolution: 1.9→1.96 Å / Redundancy: 9.2 % / Rmerge(I) obs: 3.633 / Num. unique obs: 4321 / CC1/2: 0.686 / Rpim(I) all: 1.211 / Rsym value: 3.633 / % possible all: 96.5

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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: 1.898→49.526 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 0.06 / Phase error: 29.93
RfactorNum. reflection% reflectionSelection details
Rfree0.2251 7166 4.97 %random
Rwork0.1881 ---
obs0.1899 75313 98.93 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.898→49.526 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6691 0 195 429 7315
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077105
X-RAY DIFFRACTIONf_angle_d0.9319662
X-RAY DIFFRACTIONf_dihedral_angle_d17.3574140
X-RAY DIFFRACTIONf_chiral_restr0.0491000
X-RAY DIFFRACTIONf_plane_restr0.0061216
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8979-1.91950.45422110.39824353X-RAY DIFFRACTION93
1.9195-1.9420.35892600.33614465X-RAY DIFFRACTION99
1.942-1.96570.37222430.31444585X-RAY DIFFRACTION99
1.9657-1.99060.32582780.29314561X-RAY DIFFRACTION99
1.9906-2.01680.32342090.29384580X-RAY DIFFRACTION99
2.0168-2.04440.30622110.28714571X-RAY DIFFRACTION99
2.0444-2.07360.35472520.31214659X-RAY DIFFRACTION99
2.0736-2.10460.35092480.28494535X-RAY DIFFRACTION100
2.1046-2.13750.33322010.27014665X-RAY DIFFRACTION99
2.1375-2.17250.31672010.26244596X-RAY DIFFRACTION100
2.1725-2.210.35652270.25764572X-RAY DIFFRACTION99
2.21-2.25020.38172330.3394480X-RAY DIFFRACTION97
2.2502-2.29340.3522880.29514395X-RAY DIFFRACTION98
2.2934-2.34030.30442570.22174621X-RAY DIFFRACTION100
2.3403-2.39110.25642270.21784595X-RAY DIFFRACTION100
2.3911-2.44680.28572180.21614665X-RAY DIFFRACTION100
2.4468-2.5080.28382290.21364612X-RAY DIFFRACTION100
2.508-2.57580.25582600.19644628X-RAY DIFFRACTION100
2.5758-2.65160.22582210.20764560X-RAY DIFFRACTION100
2.6516-2.73710.26342490.2124674X-RAY DIFFRACTION100
2.7371-2.83490.23512330.1964546X-RAY DIFFRACTION100
2.8349-2.94840.2372440.18824617X-RAY DIFFRACTION100
2.9484-3.08260.21552670.18764614X-RAY DIFFRACTION100
3.0826-3.24510.23392460.18224628X-RAY DIFFRACTION100
3.2451-3.44840.17622120.16484608X-RAY DIFFRACTION100
3.4484-3.71450.18882540.15654571X-RAY DIFFRACTION99
3.7145-4.08820.1832480.13774532X-RAY DIFFRACTION99
4.0882-4.67940.15462470.12974547X-RAY DIFFRACTION99
4.6794-5.8940.19152820.13754459X-RAY DIFFRACTION98
5.894-49.54250.15232100.15044394X-RAY DIFFRACTION95
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)
10.746-0.1475-0.6690.886-0.01796.7425-0.05920.1605-0.0278-0.0026-0.06950.05160.0437-0.37990.06520.2603-0.0152-0.00230.2682-0.00430.266211.2264.968122.5118
20.9157-0.2453-0.16251.05470.49333.5123-0.0252-0.04410.0498-0.1115-0.0644-0.01550.20050.1550.07580.1640.01680.04090.19290.01820.248612.33964.880360.0099
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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