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

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Basic information

Entry
Database: PDB / ID: 6aus
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with 3-(2-(6-Amino-4-methylpyridin-2-yl)ethyl)-5-(3-(methylamino)propyl)benzonitrile
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor complex heme enzyme
Function / homology
Function and homology information


positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / Nitric oxide stimulates guanylate cyclase / negative regulation of hepatic stellate cell contraction / 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 / Ion homeostasis ...positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / Nitric oxide stimulates guanylate cyclase / negative regulation of hepatic stellate cell contraction / 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 / Ion homeostasis / positive regulation of sodium ion transmembrane transport / response to nitric oxide / postsynaptic specialization, intracellular component / negative regulation of cytosolic calcium ion concentration / peptidyl-cysteine S-nitrosylation / behavioral response to cocaine / postsynaptic density, intracellular component / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of potassium ion transport / calyx of Held / negative regulation of calcium ion transport / multicellular organismal response to stress / negative regulation of serotonin uptake / sodium channel regulator activity / regulation of neurogenesis / striated muscle contraction / negative regulation of insulin secretion / regulation of postsynaptic membrane potential / response to vitamin E / nitric-oxide synthase (NADPH) / xenobiotic catabolic process / nitric-oxide synthase activity / nitric oxide mediated signal transduction / arginine catabolic process / NADPH binding / regulation of sodium ion transport / response to organonitrogen compound / T-tubule / sarcoplasmic reticulum membrane / cellular response to epinephrine stimulus / negative regulation of peptidyl-serine phosphorylation / photoreceptor inner segment / negative regulation of blood pressure / nitric oxide biosynthetic process / response to hormone / response to nutrient levels / response to activity / response to nicotine / muscle contraction / sarcoplasmic reticulum / establishment of localization in cell / secretory granule / positive regulation of long-term synaptic potentiation / female pregnancy / cell periphery / response to lead ion / sarcolemma / establishment of protein localization / potassium ion transport / response to organic cyclic compound / response to peptide hormone / Z disc / phosphoprotein binding / vasodilation / cellular response to growth factor stimulus / cellular response to mechanical stimulus / response to estrogen / calcium-dependent protein binding / calcium ion transport / FMN binding / flavin adenine dinucleotide binding / positive regulation of peptidyl-serine phosphorylation / NADP binding / ATPase binding / response to heat / scaffold protein binding / response to ethanol / nuclear membrane / negative regulation of neuron apoptotic process / mitochondrial outer membrane / transmembrane transporter binding / response to lipopolysaccharide / dendritic spine / postsynaptic density / response to hypoxia / calmodulin binding / cytoskeleton / membrane raft / negative regulation of cell population proliferation / dendrite / glutamatergic synapse / synapse / heme binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / positive regulation of DNA-templated transcription / enzyme binding / positive regulation of transcription by RNA polymerase II / protein-containing complex
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 / Chem-BYV / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.7 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 1.3Mar 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)100,14111
Polymers97,6252
Non-polymers2,5169
Water9,116506
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9740 Å2
ΔGint-87 kcal/mol
Surface area33020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.690, 110.630, 164.180
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 / Mutation: none
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, 515 molecules

#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN / Tetrahydrobiopterin


Mass: 241.247 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#4: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-BYV / 3-[2-(6-amino-4-methylpyridin-2-yl)ethyl]-5-[3-(methylamino)propyl]benzonitrile


Mass: 308.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H24N4
#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 / Water


Mass: 18.015 Da / Num. of mol.: 506 / 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: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 24, 2015 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.7→53 Å / Num. obs: 104363 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 5.1 % / CC1/2: 0.997 / Rmerge(I) obs: 0.071 / Rsym value: 0.071 / Net I/σ(I): 4.7
Reflection shellResolution: 1.7→1.74 Å / Redundancy: 4.1 % / Rmerge(I) obs: 2.159 / Mean I/σ(I) obs: 0.3 / CC1/2: 0.455 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
iMOSFLM7.1.0data reduction
Aimless0.3.11data scaling
REFMAC5.8.0049phasing
RefinementResolution: 1.7→52.42 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 0.07 / Phase error: 27.9
RfactorNum. reflection% reflectionSelection details
Rfree0.2276 5211 5.02 %random
Rwork0.1924 ---
obs0.1942 104038 99.69 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.7→52.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6659 0 175 506 7340
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077082
X-RAY DIFFRACTIONf_angle_d1.1679637
X-RAY DIFFRACTIONf_dihedral_angle_d15.2192580
X-RAY DIFFRACTIONf_chiral_restr0.074996
X-RAY DIFFRACTIONf_plane_restr0.0051217
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.71930.41363440.39896366X-RAY DIFFRACTION100
1.7193-1.73950.39263440.37616213X-RAY DIFFRACTION100
1.7395-1.76080.32983240.35786320X-RAY DIFFRACTION100
1.7608-1.78310.4113680.36186345X-RAY DIFFRACTION100
1.7831-1.80650.34833530.34556221X-RAY DIFFRACTION100
1.8065-1.83130.38793620.31766318X-RAY DIFFRACTION100
1.8313-1.85740.39663470.33256296X-RAY DIFFRACTION100
1.8574-1.88520.42063010.32246338X-RAY DIFFRACTION100
1.8852-1.91460.31613190.30016412X-RAY DIFFRACTION100
1.9146-1.9460.33263400.2786235X-RAY DIFFRACTION100
1.946-1.97960.31023710.25786331X-RAY DIFFRACTION100
1.9796-2.01560.30292910.24866312X-RAY DIFFRACTION100
2.0156-2.05430.25233480.22846306X-RAY DIFFRACTION100
2.0543-2.09630.25073310.22436308X-RAY DIFFRACTION100
2.0963-2.14180.28752670.21036438X-RAY DIFFRACTION100
2.1418-2.19170.28513010.21216343X-RAY DIFFRACTION100
2.1917-2.24650.27143370.20826369X-RAY DIFFRACTION100
2.2465-2.30720.24623930.20096198X-RAY DIFFRACTION100
2.3072-2.37510.22583250.18616374X-RAY DIFFRACTION100
2.3751-2.45180.23473180.19066363X-RAY DIFFRACTION100
2.4518-2.53940.24683170.19146298X-RAY DIFFRACTION100
2.5394-2.64110.22913220.18226318X-RAY DIFFRACTION100
2.6411-2.76130.21423160.18416344X-RAY DIFFRACTION100
2.7613-2.90680.22823400.18346334X-RAY DIFFRACTION100
2.9068-3.08890.24663640.18576264X-RAY DIFFRACTION100
3.0889-3.32740.2253200.17676294X-RAY DIFFRACTION100
3.3274-3.66220.18563320.15726392X-RAY DIFFRACTION100
3.6622-4.19190.17953330.13546288X-RAY DIFFRACTION100
4.1919-5.28060.14883810.13536292X-RAY DIFFRACTION100
5.2806-52.44470.17053100.16936245X-RAY DIFFRACTION98
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
10.7915-0.1519-0.45451.3696-0.37946.1703-0.08220.1244-0.02670.0389-0.04170.06150.1695-0.38440.06420.1718-0.0260.01550.1994-0.01930.20911.31234.861422.4349
20.7794-0.1406-0.0741.25070.34533.1439-0.01750.00480.0415-0.1381-0.0589-0.02030.11370.08540.04660.14150.03180.03130.15350.01580.195112.13514.816759.764
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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