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- PDB-9q4i: Structure of human neuronal nitric oxide synthase R354A/G357D mut... -

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Basic information

Entry
Database: PDB / ID: 9q4i
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain bound with 6-((5-(2-(ethyl(methyl)amino)ethyl)-2,3-difluorophenxy)methyl)-4-methylphridin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/INHIBITOR / nitric oxide synthase inhibitor binding / 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
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 ...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
Similarity search - Domain/homology
: / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.09 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)GM131920 United States
CitationJournal: To Be Published
Title: Highly potent, selective, and membrane permeable ether linked 2-aminopyridine-based human neuronal nitric oxide synthase inhibitors
Authors: Ansari, A. / Chrzanowski, R.T. / Li, H. / Hardy, C.D. / Poulos, T.L. / Silverman, R.B.
History
DepositionAug 20, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 10, 2025Provider: repository / Type: Initial release

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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
C: Nitric oxide synthase, brain
D: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)201,53525
Polymers195,9874
Non-polymers5,54821
Water14,538807
1
A: Nitric oxide synthase, brain
B: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,81413
Polymers97,9942
Non-polymers2,82011
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9920 Å2
ΔGint-82 kcal/mol
Surface area33850 Å2
MethodPISA
2
C: Nitric oxide synthase, brain
D: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,72212
Polymers97,9942
Non-polymers2,72810
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9800 Å2
ΔGint-81 kcal/mol
Surface area32990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.977, 163.275, 117.587
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Nitric oxide synthase, brain / Constitutive NOS / NC-NOS / NOS type I / Neuronal NOS / nNOS / Peptidyl-cysteine S-nitrosylase NOS1 / bNOS


Mass: 48996.781 Da / Num. of mol.: 4 / Mutation: R354A, G357D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NOS1 / Organ: brain / Plasmid: pET22b / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P29475, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 828 molecules

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


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN


Mass: 241.247 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H15N5O3
#4: Chemical
ChemComp-A1CN4 / 6-[(5-{2-[ethyl(methyl)amino]ethyl}-2,3-difluorophenoxy)methyl]-4-methylpyridin-2-amine


Mass: 335.392 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H23F2N3O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 807 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 3, 2023 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.09→49.53 Å / Num. obs: 113797 / % possible obs: 98.4 % / Redundancy: 4.8 % / CC1/2: 0.995 / Rmerge(I) obs: 0.143 / Rpim(I) all: 0.071 / Rrim(I) all: 0.16 / Net I/σ(I): 5.9 / Num. measured all: 542126
Reflection shellResolution: 2.09→2.13 Å / Redundancy: 3.1 % / Rmerge(I) obs: 1.903 / Num. unique obs: 4796 / CC1/2: 0.23 / Rpim(I) all: 1.198 / Rrim(I) all: 2.277 / % possible all: 84.9

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
Aimlessdata scaling
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.09→47.54 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 0.02 / Phase error: 29.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2374 11334 5.03 %random
Rwork0.1852 ---
obs0.1878 113619 98.26 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.09→47.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13538 0 380 807 14725
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00714488
X-RAY DIFFRACTIONf_angle_d0.95519717
X-RAY DIFFRACTIONf_dihedral_angle_d18.2648426
X-RAY DIFFRACTIONf_chiral_restr0.0512026
X-RAY DIFFRACTIONf_plane_restr0.0052478
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.09-2.11320.37213050.32095964X-RAY DIFFRACTION82
2.1132-2.13810.34743530.3086456X-RAY DIFFRACTION89
2.1381-2.16420.36513500.3086632X-RAY DIFFRACTION91
2.1642-2.19160.36153470.2986969X-RAY DIFFRACTION96
2.1916-2.22040.34274350.29987112X-RAY DIFFRACTION98
2.2204-2.25080.34573790.29127245X-RAY DIFFRACTION100
2.2508-2.2830.33464160.28267122X-RAY DIFFRACTION100
2.283-2.31710.33183840.27317181X-RAY DIFFRACTION100
2.3171-2.35330.31973720.27027292X-RAY DIFFRACTION100
2.3533-2.39180.32444590.257122X-RAY DIFFRACTION100
2.3918-2.43310.31233420.25667279X-RAY DIFFRACTION100
2.4331-2.47730.28833860.2457323X-RAY DIFFRACTION100
2.4773-2.5250.30054100.2377068X-RAY DIFFRACTION100
2.525-2.57650.29424050.23457265X-RAY DIFFRACTION99
2.5765-2.63250.27463690.22777238X-RAY DIFFRACTION100
2.6325-2.69380.24993500.2227220X-RAY DIFFRACTION100
2.6938-2.76110.28794090.2197299X-RAY DIFFRACTION100
2.7611-2.83580.24793620.22157195X-RAY DIFFRACTION100
2.8358-2.91920.29644000.21067309X-RAY DIFFRACTION100
2.9192-3.01340.2774040.21177219X-RAY DIFFRACTION99
3.0134-3.12110.27363780.20897074X-RAY DIFFRACTION99
3.1211-3.2460.24673720.19397301X-RAY DIFFRACTION99
3.246-3.39370.22493550.17527204X-RAY DIFFRACTION100
3.3937-3.57260.21013850.16237266X-RAY DIFFRACTION100
3.5726-3.79630.20743700.14637257X-RAY DIFFRACTION100
3.7963-4.08930.18573780.13917217X-RAY DIFFRACTION100
4.0893-4.50050.16333620.12667258X-RAY DIFFRACTION100
4.5005-5.15110.16623750.12027294X-RAY DIFFRACTION100
5.1511-6.48720.19563950.14577195X-RAY DIFFRACTION99
6.4872-47.540.19893270.1547209X-RAY DIFFRACTION99
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)
10.7745-0.0471-0.12924.03150.25231.01690.03350.02020.0877-0.007-0.0038-0.0655-0.00160.0864-0.02140.18180.0286-0.00280.24140.00790.2773262.0431350.7448-63.8626
20.66770.2571-0.08182.40170.09740.92610.03460.07260.00740.11050.00490.1778-0.0714-0.0786-0.03710.17940.0587-0.01480.25430.04270.237260.0529313.5587-63.3948
30.78950.04660.16943.87570.19720.95690.0030.0063-0.0679-0.05460.0226-0.0476-0.03050.095-0.0190.2032-0.0358-0.00120.2490.00490.2888236.1019352.5523-112.6189
40.6821-0.33930.10272.28520.01810.96490.0276-0.05610.026-0.1073-0.00160.17330.0782-0.0797-0.02630.1934-0.05960.01030.2710.04170.2512234.0556389.8244-113.0318
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)
3X-RAY DIFFRACTION3(chain C and resid 302:722)
4X-RAY DIFFRACTION4(chain D and resid 304:724)

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