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- PDB-6po8: Structure of human neuronal nitric oxide synthase R354A/G357D mut... -

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Basic information

Entry
Database: PDB / ID: 6po8
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 4-((4-(2-Amino-4-methylquinolin-7-yl)-2-(aminomethyl)phenoxy)methyl)benzonitrile
ComponentsNitric oxide synthase, brain
Keywordsoxidoreductase/oxidoreductase inhibitor / nitric oxide synthase inhibitor complex heme enzyme / OXIDOREDUCTASE / oxidoreductase-oxidoreductase inhibitor complex
Function / homology
Function and homology information


positive regulation of membrane repolarization during ventricular cardiac muscle cell action potential / negative regulation of calcium ion transport into cytosol / Nitric oxide stimulates guanylate cyclase / myoblast fusion / ROS and RNS production in phagocytes / tetrahydrobiopterin binding / arginine binding / regulation of cardiac muscle contraction by calcium ion signaling / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / synaptic signaling by nitric oxide ...positive regulation of membrane repolarization during ventricular cardiac muscle cell action potential / negative regulation of calcium ion transport into cytosol / Nitric oxide stimulates guanylate cyclase / myoblast fusion / ROS and RNS production in phagocytes / tetrahydrobiopterin binding / arginine binding / regulation of cardiac muscle contraction by calcium ion signaling / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / synaptic signaling by nitric oxide / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / negative regulation of serotonin uptake / regulation of neurogenesis / regulation of cardiac muscle contraction / nitric-oxide synthase activity / multicellular organismal response to stress / xenobiotic catabolic process / L-arginine catabolic process / striated muscle contraction / regulation of sodium ion transport / negative regulation of blood pressure / Ion homeostasis / response to hormone / nitric oxide biosynthetic process / photoreceptor inner segment / T-tubule / sarcoplasmic reticulum membrane / cell redox homeostasis / calyx of Held / sarcoplasmic reticulum / cell periphery / calcium channel regulator activity / establishment of localization in cell / sarcolemma / caveola / cellular response to growth factor stimulus / potassium ion transport / vasodilation / Z disc / calcium-dependent protein binding / calcium ion transport / FMN binding / flavin adenine dinucleotide binding / NADP binding / positive regulation of neuron apoptotic process / response to heat / scaffold protein binding / response to lipopolysaccharide / dendritic spine / transmembrane transporter binding / cytoskeleton / calmodulin binding / response to hypoxia / postsynaptic density / membrane raft / heme binding / synapse / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / nucleoplasm / nucleus / plasma membrane / cytoplasm / cytosol
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
5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-OUM / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.898 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: 2020
Title: First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.
Authors: Cinelli, M.A. / Reidl, C.T. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionJul 3, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1May 27, 2020Group: 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 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)100,1399
Polymers97,5692
Non-polymers2,5707
Water13,421745
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9560 Å2
ΔGint-125 kcal/mol
Surface area33990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.141, 121.646, 164.858
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 / 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 , 5 types, 752 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-OUM / 4-{[2-(aminomethyl)-4-(2-amino-4-methylquinolin-7-yl)phenoxy]methyl}benzonitrile


Mass: 394.468 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H22N4O / Feature type: SUBJECT OF INVESTIGATION
#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


Mass: 18.015 Da / Num. of mol.: 745 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 19, 2017 / 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: 1.898→60 Å / Num. obs: 83692 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 11.5 % / CC1/2: 0.997 / Rmerge(I) obs: 0.155 / Rpim(I) all: 0.047 / Rsym value: 0.155 / Net I/σ(I): 10.9
Reflection shellResolution: 1.9→1.95 Å / Redundancy: 11.1 % / Rmerge(I) obs: 1.947 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 4485 / CC1/2: 0.605 / Rpim(I) all: 0.603 / Rsym value: 1.947 / % possible all: 98.4

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Processing

Software
NameVersionClassification
PHENIX(1.11.1-2575_1496: ???)refinement
MOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4UH5

4uh5


Resolution: 1.898→38.492 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 0.11 / Phase error: 25.18
RfactorNum. reflection% reflectionSelection details
Rfree0.2142 7809 4.89 %random
Rwork0.1752 ---
obs0.1772 83568 99.8 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.898→38.492 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6708 0 181 745 7634
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0067163
X-RAY DIFFRACTIONf_angle_d0.9479763
X-RAY DIFFRACTIONf_dihedral_angle_d17.9624179
X-RAY DIFFRACTIONf_chiral_restr0.051004
X-RAY DIFFRACTIONf_plane_restr0.0051233
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8983-1.91990.34192380.33274921X-RAY DIFFRACTION97
1.9199-1.94250.42252150.31295145X-RAY DIFFRACTION100
1.9425-1.96620.32962750.30295008X-RAY DIFFRACTION100
1.9662-1.99110.34353090.28335022X-RAY DIFFRACTION100
1.9911-2.01730.28872690.27525072X-RAY DIFFRACTION100
2.0173-2.04490.30322510.25985043X-RAY DIFFRACTION100
2.0449-2.07410.32612760.25015128X-RAY DIFFRACTION100
2.0741-2.10510.29082570.24365041X-RAY DIFFRACTION100
2.1051-2.13790.28692830.23445015X-RAY DIFFRACTION100
2.1379-2.1730.24412300.22625151X-RAY DIFFRACTION100
2.173-2.21050.28822490.21295058X-RAY DIFFRACTION100
2.2105-2.25070.24622660.20945106X-RAY DIFFRACTION100
2.2507-2.29390.25682470.20825052X-RAY DIFFRACTION100
2.2939-2.34080.26332530.20545047X-RAY DIFFRACTION100
2.3408-2.39160.2442950.19145088X-RAY DIFFRACTION100
2.3916-2.44730.20822690.18645029X-RAY DIFFRACTION100
2.4473-2.50850.22343060.18095062X-RAY DIFFRACTION100
2.5085-2.57630.21822570.17085048X-RAY DIFFRACTION100
2.5763-2.65210.24012690.175056X-RAY DIFFRACTION100
2.6521-2.73760.20462520.17335108X-RAY DIFFRACTION100
2.7376-2.83550.23352300.16785063X-RAY DIFFRACTION100
2.8355-2.94890.21662520.16265092X-RAY DIFFRACTION100
2.9489-3.08310.21282690.16135113X-RAY DIFFRACTION100
3.0831-3.24560.1742330.1595105X-RAY DIFFRACTION100
3.2456-3.44880.20572630.15345035X-RAY DIFFRACTION100
3.4488-3.71490.18012800.14285087X-RAY DIFFRACTION100
3.7149-4.08830.16462770.13435028X-RAY DIFFRACTION100
4.0883-4.6790.15922640.12895068X-RAY DIFFRACTION100
4.679-5.89170.16512500.14925088X-RAY DIFFRACTION100
5.8917-38.49980.20672250.17245012X-RAY DIFFRACTION98
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)
10.5936-0.17680.15510.88290.23321.51690.023-0.00830.0054-0.0377-0.0659-0.01910.06690.09750.04810.1621-0.01760.04030.20860.02580.2068117.1037248.2787360.5562
20.4875-0.1608-0.02770.70550.15452.77280.05320.0571-0.0081-0.0458-0.07440.0761-0.0392-0.13030.01360.21090.02240.01760.263-0.03470.2398115.6071246.8632323.2715
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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