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

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Basic information

Entry
Database: PDB / ID: 9cvv
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain bound with 6-(3-fluoro-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 / 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 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 / 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 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 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)201,08324
Polymers195,9874
Non-polymers5,09520
Water15,241846
1
A: Nitric oxide synthase, brain
B: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,44911
Polymers97,9942
Non-polymers2,4569
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9800 Å2
ΔGint-121 kcal/mol
Surface area34040 Å2
MethodPISA
2
C: Nitric oxide synthase, brain
D: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,63313
Polymers97,9942
Non-polymers2,64011
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10340 Å2
ΔGint-121 kcal/mol
Surface area34260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.482, 118.103, 165.125
Angle α, β, γ (deg.)90.00, 90.05, 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, 866 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-A1A0H / (6M)-6-{3-fluoro-5-[(methylamino)methyl]phenyl}-4-methylpyridin-2-amine


Mass: 245.295 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H16FN3 / 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.: 846 / 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: SSRL / Beamline: BL12-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 19, 2022 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2→39.37 Å / Num. obs: 133861 / % possible obs: 98.6 % / Redundancy: 7.8 % / CC1/2: 0.992 / Rmerge(I) obs: 0.229 / Rpim(I) all: 0.086 / Rrim(I) all: 0.245 / Net I/σ(I): 6 / Num. measured all: 1047170
Reflection shellResolution: 2→2.03 Å / % possible obs: 93.5 % / Redundancy: 4.5 % / Rmerge(I) obs: 4.178 / Num. measured all: 28083 / Num. unique obs: 6265 / CC1/2: 0.297 / Rpim(I) all: 2.234 / Rrim(I) all: 4.76 / Net I/σ(I) obs: 0.5

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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→38.969 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 29.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2311 13202 5.02 %random
Rwork0.1838 ---
obs0.1861 133249 98.08 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2→38.969 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13558 0 350 846 14754
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00714400
X-RAY DIFFRACTIONf_angle_d0.91519608
X-RAY DIFFRACTIONf_dihedral_angle_d17.418414
X-RAY DIFFRACTIONf_chiral_restr0.052027
X-RAY DIFFRACTIONf_plane_restr0.0052480
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.0220.34524540.31747647X-RAY DIFFRACTION89
2.022-2.04580.32714130.28717603X-RAY DIFFRACTION91
2.0458-2.07080.33433760.29547533X-RAY DIFFRACTION88
2.0708-2.0970.33894030.2928332X-RAY DIFFRACTION97
2.097-2.12460.34114200.29258108X-RAY DIFFRACTION97
2.1246-2.15370.35044750.28778320X-RAY DIFFRACTION97
2.1537-2.18440.32374640.28478294X-RAY DIFFRACTION97
2.1844-2.2170.30794080.27518216X-RAY DIFFRACTION98
2.217-2.25170.33624610.2698239X-RAY DIFFRACTION97
2.2517-2.28860.30024400.25428473X-RAY DIFFRACTION99
2.2886-2.3280.27064870.24578336X-RAY DIFFRACTION100
2.328-2.37040.29114440.23048450X-RAY DIFFRACTION99
2.3704-2.41590.28234530.23088446X-RAY DIFFRACTION100
2.4159-2.46530.27674310.23628535X-RAY DIFFRACTION100
2.4653-2.51880.26664850.22238293X-RAY DIFFRACTION99
2.5188-2.57740.26974240.21298488X-RAY DIFFRACTION100
2.5774-2.64190.28134500.20668467X-RAY DIFFRACTION99
2.6419-2.71330.26974650.21538456X-RAY DIFFRACTION100
2.7133-2.79310.25184230.20838550X-RAY DIFFRACTION100
2.7931-2.88320.26144480.19778513X-RAY DIFFRACTION100
2.8832-2.98620.25544110.18638438X-RAY DIFFRACTION100
2.9862-3.10580.25033990.18938566X-RAY DIFFRACTION100
3.1058-3.2470.25474180.19418356X-RAY DIFFRACTION99
3.247-3.41810.22685120.17238392X-RAY DIFFRACTION100
3.4181-3.63220.20124450.15628459X-RAY DIFFRACTION100
3.6322-3.91240.19614590.14668504X-RAY DIFFRACTION100
3.9124-4.30560.16944780.13378560X-RAY DIFFRACTION100
4.3056-4.92760.16824120.12738357X-RAY DIFFRACTION99
4.9276-6.20420.18864300.14498522X-RAY DIFFRACTION100
6.2042-38.9690.17284140.15528421X-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)
10.6076-0.06510.14970.8285-0.05093.60260.01720.1282-0.001-0.0107-0.0629-0.05030.01020.0750.04210.2524-0.0037-0.02520.30880.00270.2543-10.8915-4.5408-40.4542
20.685-0.1899-0.2020.9249-0.06742.02160.004-0.0165-0.0496-0.0393-0.02780.0355-0.0516-0.12660.01840.2299-0.0161-0.04530.2643-0.03890.285-12.9644-4.2001-2.8264
30.6310.20580.19050.9256-0.11412.12690.00580.0190.04140.0392-0.02320.02250.0581-0.1190.00980.22860.00760.04240.2666-0.04660.283613.3481-54.1577-79.7235
40.56720.1091-0.04950.7797-0.04313.34670.0156-0.09560.00810.0068-0.0667-0.05670.03620.07480.04620.27560.01460.02560.33770.00530.278515.3289-53.7345-42.1165
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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