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

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Basic information

Entry
Database: PDB / ID: 6aur
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with 6-(3-Fluoro-5-(3-(methylamino)propyl)phenethyl)-4-methylpyridin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor complex heme enzyme
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 / response to hormone / behavioral response to cocaine / nitric oxide metabolic process / nitric oxide biosynthetic process / photoreceptor inner segment / T-tubule / cellular response to epinephrine stimulus / 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
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 / 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 / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
ACETATE ION / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-W68 / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.75 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: 2017
Title: Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker.
Authors: Do, H.T. / Wang, H.Y. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionSep 1, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 11, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 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)100,12711
Polymers97,6252
Non-polymers2,5029
Water11,692649
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9750 Å2
ΔGint-87 kcal/mol
Surface area33020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.170, 110.900, 164.230
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 / Fragment: UNP residues 297-718
Source method: isolated from a genetically manipulated source
Details: Residues 339 to 349 are disordered. The N-terminal residues 297 and 298 as well as C-terminal residues 717 and 718 are not observed in density
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Nos1, Bnos / Organ: brain / Plasmid: pCWori / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P29476, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 658 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-W68 / 6-(2-{3-fluoro-5-[3-(methylamino)propyl]phenyl}ethyl)-4-methylpyridin-2-amine


Mass: 301.402 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H24FN3
#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.: 649 / 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: brick
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
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 0.97946 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Aug 2, 2015 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. obs: 96987 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 5.1 % / CC1/2: 0.997 / Rmerge(I) obs: 0.091 / Rsym value: 0.091 / Net I/σ(I): 8.7
Reflection shellResolution: 1.75→1.8 Å / Redundancy: 4.4 % / Rmerge(I) obs: 1.278 / Mean I/σ(I) obs: 1 / Num. unique obs: 4699 / CC1/2: 0.427 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
iMOSFLM7.2.0data reduction
Aimless0.5.12data scaling
REFMAC5.8.0049phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1OM4

1om4


Resolution: 1.75→45.37 Å / SU ML: 0.22 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 24.31
RfactorNum. reflection% reflectionSelection details
Rfree0.2125 4840 5.02 %random
Rwork0.1817 ---
obs0.1832 96834 99.9 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.75→45.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6659 0 173 649 7481
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077069
X-RAY DIFFRACTIONf_angle_d1.1839618
X-RAY DIFFRACTIONf_dihedral_angle_d14.9432574
X-RAY DIFFRACTIONf_chiral_restr0.074994
X-RAY DIFFRACTIONf_plane_restr0.0051215
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.76990.37253340.35155742X-RAY DIFFRACTION100
1.7699-1.79070.34113360.345917X-RAY DIFFRACTION100
1.7907-1.81260.34833190.32445810X-RAY DIFFRACTION100
1.8126-1.83550.35293180.31235868X-RAY DIFFRACTION100
1.8355-1.85970.34593520.31275881X-RAY DIFFRACTION100
1.8597-1.88510.33712590.29995878X-RAY DIFFRACTION100
1.8851-1.91210.30742930.28145897X-RAY DIFFRACTION100
1.9121-1.94060.29243280.26235842X-RAY DIFFRACTION100
1.9406-1.97090.29553150.26115832X-RAY DIFFRACTION100
1.9709-2.00320.29953340.25475937X-RAY DIFFRACTION100
2.0032-2.03780.28342840.24465793X-RAY DIFFRACTION100
2.0378-2.07480.26763180.22195915X-RAY DIFFRACTION100
2.0748-2.11470.27552820.21365899X-RAY DIFFRACTION100
2.1147-2.15790.25922660.20425917X-RAY DIFFRACTION100
2.1579-2.20480.28042760.20245878X-RAY DIFFRACTION100
2.2048-2.25610.24693000.19025874X-RAY DIFFRACTION100
2.2561-2.31250.22643760.18185838X-RAY DIFFRACTION100
2.3125-2.37510.20522990.1745899X-RAY DIFFRACTION100
2.3751-2.44490.24483080.1765840X-RAY DIFFRACTION100
2.4449-2.52390.25393020.17735899X-RAY DIFFRACTION100
2.5239-2.61410.19273150.16795886X-RAY DIFFRACTION100
2.6141-2.71870.21722840.17345885X-RAY DIFFRACTION100
2.7187-2.84240.22513020.17435861X-RAY DIFFRACTION100
2.8424-2.99230.19293230.16575905X-RAY DIFFRACTION100
2.9923-3.17970.21363330.17345816X-RAY DIFFRACTION100
3.1797-3.42510.19682880.16755926X-RAY DIFFRACTION100
3.4251-3.76960.17923190.14235862X-RAY DIFFRACTION100
3.7696-4.31470.15143010.13355896X-RAY DIFFRACTION100
4.3147-5.43470.14813490.13145820X-RAY DIFFRACTION100
5.4347-45.38520.14282990.15845885X-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)
10.7239-0.0199-0.60980.8553-0.10475.0675-0.04610.2175-0.0081-0.079-0.03450.0457-0.0868-0.44020.03310.1227-0.00580.00070.1765-0.00410.150811.42384.882722.4951
20.6656-0.0706-0.13720.86820.38832.2398-0.0379-0.02580.0268-0.0677-0.0384-0.00830.08050.07920.06110.08590.00040.02410.1120.01550.156312.12744.829959.7699
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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