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- PDB-5uo1: Structure of human neuronal nitric oxide synthase heme domain in ... -

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Basic information

Entry
Database: PDB / ID: 5uo1
TitleStructure of human neuronal nitric oxide synthase heme domain in complex with 3-[(2-aminoquinolin-7-yl)methoxy]-5-((methylamino)methyl)benzonitrile
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / nitric / oxide / synthase / inhibitor / complex / heme / enzyme / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of calcium ion transport into cytosol / neurotransmitter biosynthetic process / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / myoblast fusion / Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / tetrahydrobiopterin binding / arginine binding / retrograde trans-synaptic signaling by nitric oxide / positive regulation of sodium ion transmembrane transport ...negative regulation of calcium ion transport into cytosol / neurotransmitter biosynthetic process / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / myoblast fusion / Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / tetrahydrobiopterin binding / arginine binding / retrograde trans-synaptic signaling by nitric oxide / positive regulation of sodium ion transmembrane transport / positive regulation of the force of heart contraction / cadmium ion binding / negative regulation of serotonin uptake / striated muscle contraction / peptidyl-cysteine S-nitrosylation / negative regulation of potassium ion transport / regulation of cardiac muscle contraction / regulation of sodium ion transport / negative regulation of calcium ion transport / multicellular organismal response to stress / sodium channel regulator activity / negative regulation of hydrolase activity / Ion homeostasis / nitric-oxide synthase (NADPH) / positive regulation of guanylate cyclase activity / negative regulation of blood pressure / nitric oxide mediated signal transduction / xenobiotic catabolic process / vesicle membrane / nitric-oxide synthase activity / arginine catabolic process / response to hormone / regulation of ryanodine-sensitive calcium-release channel activity / photoreceptor inner segment / positive regulation of histone acetylation / nitric oxide biosynthetic process / sarcoplasmic reticulum / muscle contraction / cell redox homeostasis / cell periphery / sarcolemma / cellular response to growth factor stimulus / vasodilation / calcium-dependent protein binding / FMN binding / scaffold protein binding / flavin adenine dinucleotide binding / NADP binding / response to heat / transmembrane transporter binding / positive regulation of peptidyl-serine phosphorylation / response to lipopolysaccharide / calmodulin binding / dendritic spine / response to hypoxia / postsynaptic density / cytoskeleton / oxidoreductase activity / membrane raft / synapse / heme binding / perinuclear region of cytoplasm / positive regulation of transcription, DNA-templated / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / nucleoplasm / plasma membrane / nucleus / cytosol / cytoplasm
Similarity search - Function
Nitric-oxide synthase, eukaryote / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 3 superfamily ...Nitric-oxide synthase, eukaryote / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 3 superfamily / Nitric oxide synthase, N-terminal / Nitric oxide synthase, oxygenase domain / Nitric oxide synthase, N-terminal domain superfamily / 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 / Oxidoreductase FAD/NAD(P)-binding / Oxidoreductase NAD-binding domain / Flavodoxin-like domain profile. / Flavodoxin/nitric oxide synthase / Ferredoxin reductase-type FAD binding domain profile. / Ferredoxin-NADP reductase (FNR), nucleotide-binding domain / FAD-binding domain, ferredoxin reductase-type / 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
Chem-8EV / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase, brain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.9 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)GM United States
CitationJournal: J. Med. Chem. / Year: 2017
Title: Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.
Authors: Cinelli, M.A. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionJan 31, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2017Provider: repository / Type: Initial release
Revision 1.1May 24, 2017Group: Database references
Revision 1.2Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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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)100,07910
Polymers97,5692
Non-polymers2,5108
Water12,953719
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9560 Å2
ΔGint-84 kcal/mol
Surface area33900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.290, 122.460, 164.980
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 / / Constitutive NOS / NC-NOS / NOS type I / Neuronal NOS / nNOS / Peptidyl-cysteine S-nitrosylase NOS1 / bNOS


Mass: 48784.496 Da / Num. of mol.: 2 / Fragment: UNP residues 302-722 / Mutation: R354A, G357D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NOS1 / Organ: brain / Plasmid: pCWori / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P29475, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 727 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-8EV / 3-[(2-aminoquinolin-7-yl)methoxy]-5-[(methylamino)methyl]benzonitrile


Mass: 318.372 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H18N4O
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#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.: 719 / 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: 2.74 Å3/Da / Density % sol: 55.2 % / Description: plate
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: 8% PEG3350, 35 mM citric acid, 65 mM Bis-Tris propane, 10% glycerol, 5 mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 11, 2015 / Details: mirrors
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→60 Å / Num. obs: 84367 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 4.8 % / CC1/2: 0.995 / Rmerge(I) obs: 0.113 / Rsym value: 0.113 / Net I/σ(I): 7.9
Reflection shellResolution: 1.9→1.95 Å / Redundancy: 4.8 % / Rmerge(I) obs: 1.622 / Mean I/σ(I) obs: 1 / Num. unique all: 4452 / CC1/2: 0.492 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
iMOSFLM7.1.0data reduction
Aimless0.3.11data scaling
REFMAC5.8.0049phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 4UH5
Resolution: 1.9→50.167 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 0.04 / Phase error: 24.72
RfactorNum. reflection% reflectionSelection details
Rfree0.2167 4126 4.88 %random
Rwork0.1767 ---
obs0.1786 84241 99.79 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.9→50.167 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6698 0 175 719 7592
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077112
X-RAY DIFFRACTIONf_angle_d1.1219682
X-RAY DIFFRACTIONf_dihedral_angle_d14.8372587
X-RAY DIFFRACTIONf_chiral_restr0.07998
X-RAY DIFFRACTIONf_plane_restr0.0041222
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.92160.39552400.35825168X-RAY DIFFRACTION100
1.9216-1.94420.37642220.34115184X-RAY DIFFRACTION100
1.9442-1.96790.33022760.32014992X-RAY DIFFRACTION100
1.9679-1.99280.34982890.30245103X-RAY DIFFRACTION100
1.9928-2.01910.3292850.29185140X-RAY DIFFRACTION100
2.0191-2.04670.32972540.27095016X-RAY DIFFRACTION100
2.0467-2.0760.31932640.27285145X-RAY DIFFRACTION100
2.076-2.10690.33592680.26225098X-RAY DIFFRACTION100
2.1069-2.13990.25313020.24925045X-RAY DIFFRACTION100
2.1399-2.1750.2952230.23555192X-RAY DIFFRACTION100
2.175-2.21250.2842470.2195089X-RAY DIFFRACTION100
2.2125-2.25270.24752690.22085123X-RAY DIFFRACTION100
2.2527-2.2960.26422480.21515099X-RAY DIFFRACTION100
2.296-2.34290.25362520.20455125X-RAY DIFFRACTION100
2.3429-2.39380.23342940.19015074X-RAY DIFFRACTION100
2.3938-2.44950.22652700.19065093X-RAY DIFFRACTION100
2.4495-2.51080.24763060.18755109X-RAY DIFFRACTION100
2.5108-2.57860.21212580.17385073X-RAY DIFFRACTION100
2.5786-2.65450.24332750.17245097X-RAY DIFFRACTION100
2.6545-2.74020.21082670.17415117X-RAY DIFFRACTION100
2.7402-2.83810.21262220.16295146X-RAY DIFFRACTION100
2.8381-2.95170.18372550.15815099X-RAY DIFFRACTION100
2.9517-3.08610.19222670.16225148X-RAY DIFFRACTION100
3.0861-3.24870.22222470.16585123X-RAY DIFFRACTION100
3.2487-3.45220.22042510.15875087X-RAY DIFFRACTION100
3.4522-3.71870.18082860.13925112X-RAY DIFFRACTION100
3.7187-4.09280.17062750.13245063X-RAY DIFFRACTION100
4.0928-4.68460.15052620.12335074X-RAY DIFFRACTION99
4.6846-5.90070.17862550.13955101X-RAY DIFFRACTION100
5.9007-50.18450.18572260.15445086X-RAY DIFFRACTION99
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)
10.6211-0.15240.07440.7910.18041.3970.00480.00950.0251-0.0359-0.0355-0.01920.06450.07330.03070.1409-0.01340.02490.17950.02970.1846117.3423249.8342360.5255
20.4758-0.1356-0.06240.70840.10962.250.06440.0580.0077-0.0158-0.07190.0531-0.0564-0.10930.01350.19060.00920.02970.2344-0.01980.213115.9555248.7251323.2496
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 302:721)
2X-RAY DIFFRACTION2(chain B and resid 304:721)

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