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- PDB-6av5: Structure of human neuronal nitric oxide synthase R354A/G356D mut... -

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Basic information

Entry
Database: PDB / ID: 6av5
TitleStructure of human neuronal nitric oxide synthase R354A/G356D mutant heme domain in complex with 6-(2-(5-Fluoro-3'-((methylamino)methyl)-[1,1'-biphenyl]-3-yl)ethyl)-4-methylpyridin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/inhibitor / nitric oxide synthase inhibitor 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 / negative regulation of calcium ion transport / regulation of sodium 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 / nitric oxide mediated signal transduction / xenobiotic catabolic process / vesicle membrane / nitric-oxide synthase activity / arginine catabolic process / negative regulation of blood pressure / regulation of ryanodine-sensitive calcium-release channel activity / response to hormone / photoreceptor inner segment / nitric oxide biosynthetic process / sarcoplasmic reticulum / positive regulation of histone acetylation / 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 / transmembrane transporter binding / response to heat / 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 DNA-templated transcription / 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 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 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 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / 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, N-terminal / Nitric oxide synthase (NOS) signature. / Nitric oxide synthase, N-terminal domain superfamily / NADPH-cytochrome p450 reductase, FAD-binding, alpha-helical domain superfamily / FAD binding domain / Sulfite reductase [NADPH] flavoprotein alpha-component-like, FAD-binding / Flavodoxin-like / Flavoprotein pyridine nucleotide cytochrome reductase / Flavodoxin / Oxidoreductase NAD-binding domain / Oxidoreductase FAD/NAD(P)-binding / Flavodoxin-like domain profile. / Flavodoxin/nitric oxide synthase / 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
5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-W82 / 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)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 1.2Jan 1, 2020Group: 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)100,0499
Polymers97,5692
Non-polymers2,4807
Water10,287571
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9320 Å2
ΔGint-84 kcal/mol
Surface area33730 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.530, 122.300, 164.360
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
Source method: isolated from a genetically manipulated source
Details: Residues 344 to 351 are disordered / Source: (gene. exp.) Homo sapiens (human) / Gene: NOS1 / Organ: brain / Plasmid: pCWori / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P29475, nitric-oxide synthase (NADPH)

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Non-polymers , 5 types, 578 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-W82 / 6-(2-{5-fluoro-3'-[(methylamino)methyl][1,1'-biphenyl]-3-yl}ethyl)-4-methylpyridin-2-amine


Mass: 349.444 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24FN3
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 571 / 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 35mM citric acid 65mM Bis-Tris-Propane 10% glycerol 5mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 1.195 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jul 28, 2017 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.195 Å / Relative weight: 1
ReflectionResolution: 1.9→60 Å / Num. obs: 84443 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 6.1 % / CC1/2: 0.997 / Rmerge(I) obs: 0.114 / Rpim(I) all: 0.077 / Rsym value: 0.114 / Net I/σ(I): 8.8
Reflection shellResolution: 1.9→1.95 Å / Redundancy: 6 % / Rmerge(I) obs: 1.688 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 4412 / CC1/2: 0.462 / Rpim(I) all: 1.171 / Rsym value: 1.688 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.11.1-2575_1496: ???)refinement
iMOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4UH5
Resolution: 1.9→38.95 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 26.68
RfactorNum. reflection% reflectionSelection details
Rfree0.2186 4131 4.88 %random
Rwork0.1841 ---
obs0.1858 84326 99.95 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.9→38.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6699 0 173 571 7443
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077124
X-RAY DIFFRACTIONf_angle_d0.9779703
X-RAY DIFFRACTIONf_dihedral_angle_d17.7944157
X-RAY DIFFRACTIONf_chiral_restr0.0511000
X-RAY DIFFRACTIONf_plane_restr0.0051227
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.92160.39452470.38775084X-RAY DIFFRACTION100
1.9216-1.94420.41762010.36835240X-RAY DIFFRACTION100
1.9442-1.96790.37132810.35985058X-RAY DIFFRACTION100
1.9679-1.99280.37153040.34225046X-RAY DIFFRACTION100
1.9928-2.01910.36842890.32555132X-RAY DIFFRACTION100
2.0191-2.04670.33112390.31665062X-RAY DIFFRACTION100
2.0467-2.07590.32382540.29545139X-RAY DIFFRACTION100
2.0759-2.10690.31472770.28365123X-RAY DIFFRACTION100
2.1069-2.13990.28032970.27634999X-RAY DIFFRACTION100
2.1399-2.17490.3292250.26585170X-RAY DIFFRACTION100
2.1749-2.21240.30492520.24755149X-RAY DIFFRACTION100
2.2124-2.25270.26882650.24075075X-RAY DIFFRACTION100
2.2527-2.2960.28672560.22295142X-RAY DIFFRACTION100
2.296-2.34280.25272310.21075076X-RAY DIFFRACTION100
2.3428-2.39380.22153140.19835130X-RAY DIFFRACTION100
2.3938-2.44950.23612740.19945037X-RAY DIFFRACTION100
2.4495-2.51070.23953040.18925116X-RAY DIFFRACTION100
2.5107-2.57860.21232570.18425077X-RAY DIFFRACTION100
2.5786-2.65440.24812700.17965107X-RAY DIFFRACTION100
2.6544-2.74010.232700.17585123X-RAY DIFFRACTION100
2.7401-2.8380.21272260.17195149X-RAY DIFFRACTION100
2.838-2.95160.20152500.17345083X-RAY DIFFRACTION100
2.9516-3.08590.20292700.16245142X-RAY DIFFRACTION100
3.0859-3.24850.21892460.16495152X-RAY DIFFRACTION100
3.2485-3.45190.21112510.16575076X-RAY DIFFRACTION100
3.4519-3.71820.182840.14375111X-RAY DIFFRACTION100
3.7182-4.0920.16262750.13565092X-RAY DIFFRACTION100
4.092-4.68330.15072710.12775103X-RAY DIFFRACTION100
4.6833-5.89720.18682510.145125X-RAY DIFFRACTION100
5.8972-38.95860.16892290.15695123X-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)
10.6456-0.17620.03820.86810.18172.38260.0068-0.02220.0215-0.0435-0.0686-0.02180.16620.15570.05870.1769-0.00680.03310.24590.03440.2361117.9304249.5942359.3189
20.5852-0.2313-0.19050.7670.20833.53830.03910.0909-0.0049-0.0318-0.06330.07440.049-0.19110.01860.23410.00930.02180.2929-0.02380.2629116.5173248.3435322.1336
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 302:722)
2X-RAY DIFFRACTION2(chain B and resid 304:721)

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