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- PDB-6nhb: Structure of human neuronal nitric oxide synthase R354A/G357D mut... -

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Basic information

Entry
Database: PDB / ID: 6nhb
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 6-(5-(2-((2S,4R)-4-ethoxy-1-methylpyrrolidin-2-yl)ethyl)-2,3-difluorophenethyl)-4-methylpyridin-2-amine
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 / myoblast fusion / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / neurotransmitter biosynthetic process / 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 / myoblast fusion / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / neurotransmitter biosynthetic process / 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 / negative regulation of potassium ion transport / cadmium ion binding / negative regulation of serotonin uptake / regulation of sodium ion transport / sodium channel regulator activity / striated muscle contraction / peptidyl-cysteine S-nitrosylation / negative regulation of calcium ion transport / regulation of cardiac muscle contraction / regulation of cardiac conduction / negative regulation of hydrolase activity / multicellular organismal response to stress / xenobiotic catabolic process => GO:0042178 / Ion homeostasis / nitric-oxide synthase (NADPH) / positive regulation of guanylate cyclase activity / negative regulation of blood pressure / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen / nitric oxide mediated signal transduction / nitric-oxide synthase activity / vesicle membrane / arginine catabolic process / regulation of ryanodine-sensitive calcium-release channel activity / response to hormone / positive regulation of histone acetylation / sarcoplasmic reticulum / nitric oxide biosynthetic process / cell periphery / cell redox homeostasis / photoreceptor inner segment / sarcolemma / muscle contraction / cellular response to growth factor stimulus / vasodilation / calcium-dependent protein binding / FMN binding / scaffold protein binding / flavin adenine dinucleotide binding / response to heat / transmembrane transporter binding / NADP binding / positive regulation of peptidyl-serine phosphorylation / response to lipopolysaccharide / calmodulin binding / dendritic spine / response to hypoxia / postsynaptic density / cytoskeleton / oxidoreductase activity / synapse / membrane raft / heme binding / positive regulation of transcription, DNA-templated / perinuclear region of cytoplasm / 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 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 3 / Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / Nitric oxide synthase, oxygenase domain / Nitric oxide synthase (NOS) signature. / Nitric oxide synthase, N-terminal ...Nitric-oxide synthase, eukaryote / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 3 / Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / Nitric oxide synthase, oxygenase domain / Nitric oxide synthase (NOS) signature. / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain superfamily / Sulfite reductase [NADPH] flavoprotein alpha-component-like, FAD-binding / FAD binding domain / NADPH-cytochrome p450 reductase, FAD-binding, alpha-helical domain superfamily / 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. / FAD-binding domain, ferredoxin reductase-type / Ferredoxin-NADP reductase (FNR), nucleotide-binding domain / 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
5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-KNS / Nitric oxide synthase, brain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.03 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

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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)100,43312
Polymers97,5692
Non-polymers2,86410
Water6,035335
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10110 Å2
ΔGint-83 kcal/mol
Surface area34040 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)52.024, 122.945, 164.407
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, 345 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-KNS / 6-[2-(5-{2-[(2S,4R)-4-ethoxy-1-methylpyrrolidin-2-yl]ethyl}-2,3-difluorophenyl)ethyl]-4-methylpyridin-2-amine


Mass: 403.509 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H31F2N3O
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 3 / 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.: 335 / 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: plates
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 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 8, 2018
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: 2.03→60 Å / Num. obs: 69176 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 7.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.132 / Rpim(I) all: 0.053 / Rsym value: 0.132 / Net I/σ(I): 9.5
Reflection shellResolution: 2.03→2.1 Å / Redundancy: 7 % / Rmerge(I) obs: 2.666 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 4420 / CC1/2: 0.334 / Rpim(I) all: 1.079 / Rsym value: 2.666 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.11.1-2575_1496: ???)refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 5AD7
Resolution: 2.03→49.23 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 0.14 / Phase error: 31.54
RfactorNum. reflection% reflectionSelection details
Rfree0.2459 6417 4.88 %random
Rwork0.1989 ---
obs0.2012 69026 99.86 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.03→49.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6766 0 197 335 7298
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077217
X-RAY DIFFRACTIONf_angle_d0.9769828
X-RAY DIFFRACTIONf_dihedral_angle_d18.084228
X-RAY DIFFRACTIONf_chiral_restr0.0511017
X-RAY DIFFRACTIONf_plane_restr0.0061239
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.03-2.05310.39262010.32374230X-RAY DIFFRACTION100
2.0531-2.07720.41622260.34544184X-RAY DIFFRACTION100
2.0772-2.10260.40272170.34894077X-RAY DIFFRACTION100
2.1026-2.12920.41122520.32914133X-RAY DIFFRACTION100
2.1292-2.15720.36581930.34094224X-RAY DIFFRACTION100
2.1572-2.18670.35152100.32314158X-RAY DIFFRACTION100
2.1867-2.2180.3451830.30084157X-RAY DIFFRACTION100
2.218-2.25110.36832190.33944199X-RAY DIFFRACTION100
2.2511-2.28630.3522060.3314155X-RAY DIFFRACTION100
2.2863-2.32370.37971930.30354189X-RAY DIFFRACTION100
2.3237-2.36380.37262380.29864207X-RAY DIFFRACTION100
2.3638-2.40680.31252340.27394067X-RAY DIFFRACTION100
2.4068-2.45310.29132300.2844145X-RAY DIFFRACTION100
2.4531-2.50320.34682470.28084158X-RAY DIFFRACTION100
2.5032-2.55760.32832130.26594151X-RAY DIFFRACTION100
2.5576-2.61710.33632120.25334219X-RAY DIFFRACTION100
2.6171-2.68250.28922370.25024089X-RAY DIFFRACTION100
2.6825-2.7550.28751930.24524190X-RAY DIFFRACTION100
2.755-2.83610.30361970.22874213X-RAY DIFFRACTION100
2.8361-2.92760.24152120.21374164X-RAY DIFFRACTION100
2.9276-3.03230.27381900.20454217X-RAY DIFFRACTION100
3.0323-3.15360.242130.20714151X-RAY DIFFRACTION100
3.1536-3.29710.25352100.19564142X-RAY DIFFRACTION100
3.2971-3.47090.24612100.18714207X-RAY DIFFRACTION100
3.4709-3.68830.20442360.15784155X-RAY DIFFRACTION100
3.6883-3.9730.18252350.15174165X-RAY DIFFRACTION100
3.973-4.37260.19622040.13994161X-RAY DIFFRACTION100
4.3726-5.00480.17432190.1424149X-RAY DIFFRACTION100
5.0048-6.30340.21262020.16784198X-RAY DIFFRACTION100
6.3034-49.24420.21141850.16264196X-RAY DIFFRACTION100
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)
10.8138-0.26060.13831.1270.25982.19410.0174-0.0158-0.0168-0.0009-0.1163-0.01310.09420.0510.08910.2691-0.05670.06130.3310.02990.3278117.0137250.9505359.8975
20.5933-0.0594-0.04371.18790.22533.35460.06420.1243-0.0501-0.1193-0.15870.1551-0.0142-0.17490.07680.31390.02380.010.4424-0.06980.3562115.2445249.6514322.6491
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 302:722)
2X-RAY DIFFRACTION2(chain B and resid 304:722)

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