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

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Basic information

Entry
Database: PDB / ID: 9cvy
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain bound with 6-(2,3-difluoro-5-((methylamino)methyl)phenyl)-4-methylpyridin-2-amine dihydrochloride
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 / peptidyl-cysteine S-nitrosylase activity / 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 ...positive regulation of membrane repolarization during ventricular cardiac muscle cell action potential / negative regulation of calcium ion transport into cytosol / peptidyl-cysteine S-nitrosylase activity / 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 / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of sodium ion transmembrane transport / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of potassium ion transport / negative regulation of calcium ion transport / nitric oxide mediated signal transduction / nitric-oxide synthase (NADPH) / sodium channel regulator activity / negative regulation of serotonin uptake / 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 / Ion homeostasis / negative regulation of blood pressure / response to hormone / photoreceptor inner segment / calcium channel regulator activity / nitric oxide biosynthetic process / cell redox homeostasis / sarcoplasmic reticulum / cell periphery / sarcolemma / cellular response to growth factor stimulus / calcium-dependent protein binding / vasodilation / positive regulation of neuron apoptotic process / FMN binding / flavin adenine dinucleotide binding / NADP binding / response to heat / scaffold protein binding / dendritic spine / response to lipopolysaccharide / transmembrane transporter binding / cytoskeleton / response to hypoxia / calmodulin binding / postsynaptic density / membrane raft / synapse / heme binding / 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 / cytosol / cytoplasm
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 / 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
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: 2.391 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: Bioorg.Med.Chem. / Year: 2025
Title: Truncated pyridinylbenzylamines: Potent, selective, and highly membrane permeable inhibitors of human neuronal nitric oxide synthase.
Authors: Vasu, D. / Do, H.T. / Li, H. / Hardy, C.D. / Poulos, T.L. / Silverman, R.B.
History
DepositionJul 29, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 30, 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)201,15524
Polymers195,9874
Non-polymers5,16720
Water7,819434
1
A: Nitric oxide synthase, brain
B: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,48511
Polymers97,9942
Non-polymers2,4929
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9880 Å2
ΔGint-82 kcal/mol
Surface area34350 Å2
MethodPISA
2
C: Nitric oxide synthase, brain
D: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,66913
Polymers97,9942
Non-polymers2,67611
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9880 Å2
ΔGint-80 kcal/mol
Surface area33900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.243, 164.441, 118.642
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, 454 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 / Comment: neurotransmitter*YM
#4: Chemical
ChemComp-A1A0B / (6M)-6-{2,3-difluoro-5-[(methylamino)methyl]phenyl}-4-methylpyridin-2-amine


Mass: 263.286 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H15F2N3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / 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.: 434 / 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: 278 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: Oct 17, 2022 / 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: 2.39→48.11 Å / Num. obs: 78289 / % possible obs: 99.1 % / Redundancy: 4.8 % / CC1/2: 0.953 / Rmerge(I) obs: 0.39 / Rpim(I) all: 0.195 / Rrim(I) all: 0.438 / Net I/σ(I): 3 / Num. measured all: 375114
Reflection shellResolution: 2.39→2.44 Å / % possible obs: 85.9 % / Redundancy: 3.6 % / Rmerge(I) obs: 3.516 / Num. measured all: 13595 / Num. unique obs: 3829 / CC1/2: 0.114 / Rpim(I) all: 2.008 / Rrim(I) all: 4.076 / Net I/σ(I) obs: 0.3

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1.11.1_2575refinement
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.391→48.107 Å / SU ML: 0.48 / Cross valid method: FREE R-VALUE / σ(F): 0.58 / Phase error: 33.36 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2762 7167 4.96 %random
Rwork0.2086 ---
obs0.212 73944 92.5 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.391→48.107 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13551 0 354 434 14339
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00914379
X-RAY DIFFRACTIONf_angle_d1.11519573
X-RAY DIFFRACTIONf_dihedral_angle_d18.3828392
X-RAY DIFFRACTIONf_chiral_restr0.0542019
X-RAY DIFFRACTIONf_plane_restr0.0072473
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.391-2.41790.3541780.34671339X-RAY DIFFRACTION27
2.4179-2.44630.36831330.31852930X-RAY DIFFRACTION59
2.4463-2.47620.39471860.31883516X-RAY DIFFRACTION71
2.4762-2.50750.35991960.33923945X-RAY DIFFRACTION79
2.5075-2.54050.35522440.3464228X-RAY DIFFRACTION87
2.5405-2.57530.412640.32294490X-RAY DIFFRACTION92
2.5753-2.61210.34112940.33124773X-RAY DIFFRACTION95
2.6121-2.65110.35362140.34024667X-RAY DIFFRACTION95
2.6511-2.69250.41092290.34734845X-RAY DIFFRACTION97
2.6925-2.73660.39052550.30884840X-RAY DIFFRACTION97
2.7366-2.78380.40272760.28634808X-RAY DIFFRACTION98
2.7838-2.83440.29592360.28064845X-RAY DIFFRACTION99
2.8344-2.88890.32682620.29954957X-RAY DIFFRACTION99
2.8889-2.94790.35672700.30184855X-RAY DIFFRACTION99
2.9479-3.0120.37172710.28464830X-RAY DIFFRACTION99
3.012-3.0820.35712760.284998X-RAY DIFFRACTION99
3.082-3.15910.36222410.284828X-RAY DIFFRACTION99
3.1591-3.24450.32682690.24244942X-RAY DIFFRACTION99
3.2445-3.340.30112110.22154796X-RAY DIFFRACTION98
3.34-3.44770.31622590.2314893X-RAY DIFFRACTION97
3.4477-3.57090.2762570.21294803X-RAY DIFFRACTION98
3.5709-3.71380.24882440.18854910X-RAY DIFFRACTION99
3.7138-3.88280.26712720.17124855X-RAY DIFFRACTION99
3.8828-4.08740.20952470.16014942X-RAY DIFFRACTION99
4.0874-4.34330.22662450.13195005X-RAY DIFFRACTION100
4.3433-4.67840.17152450.12144873X-RAY DIFFRACTION99
4.6784-5.14880.18762540.1284927X-RAY DIFFRACTION99
5.1488-5.89260.22992660.15044903X-RAY DIFFRACTION99
5.8926-7.41970.22942510.15524830X-RAY DIFFRACTION98
7.4197-48.1070.19892220.14474958X-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)
10.5214-0.022-0.07652.43020.19650.55470.05330.00010.06150.030.0247-0.07040.0020.032-0.04690.20150.00660.00530.2516-0.00310.2661263.3238353.1164-64.4896
20.37390.1468-0.15271.52320.07230.7122-0.00080.0354-0.01790.04770.02480.0717-0.0287-0.0259-0.03660.23730.0311-0.02630.28850.01950.2781261.3897315.7679-63.9864
30.48620.1806-0.02232.29710.16190.5444-0.0106-0.0022-0.04020.00110.0258-0.093-0.02520.051-0.01750.2008-0.0011-0.01790.2330.0010.2397237.261355.0788-113.6118
40.3818-0.15650.0981.41540.20860.69140.0094-0.052-0.0394-0.06330.01120.10190.0463-0.0165-0.02770.2219-0.03160.00890.28260.03660.2758235.2719392.584-113.9395
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 303:722)
2X-RAY DIFFRACTION2(chain B and resid 304:722)
3X-RAY DIFFRACTION3(chain C and resid 305:722)
4X-RAY DIFFRACTION4(chain D and resid 304:722)

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