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- PDB-9cw3: Structure of human neuronal nitric oxide synthase R354A/G357D mut... -

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Basic information

Entry
Database: PDB / ID: 9cw3
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain bound with 6-(5-((4,4-difluoropiperidin-1-yl)methyl)-2,3-difluorophenyl)-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: 2.19 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)201,51524
Polymers195,9874
Non-polymers5,52820
Water12,070670
1
A: Nitric oxide synthase, brain
B: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,75712
Polymers97,9942
Non-polymers2,76410
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9970 Å2
ΔGint-84 kcal/mol
Surface area33970 Å2
MethodPISA
2
C: Nitric oxide synthase, brain
D: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,75712
Polymers97,9942
Non-polymers2,76410
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9960 Å2
ΔGint-82 kcal/mol
Surface area34220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.462, 52.052, 164.763
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, 690 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-A1A0A / (6M)-6-{5-[(4,4-difluoropiperidin-1-yl)methyl]-2,3-difluorophenyl}-4-methylpyridin-2-amine


Mass: 353.357 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H19F4N3 / 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.: 670 / 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: Dec 18, 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: 2.19→49.63 Å / Num. obs: 104426 / % possible obs: 99.9 % / Redundancy: 10.2 % / CC1/2: 0.985 / Rmerge(I) obs: 0.556 / Rpim(I) all: 0.181 / Rrim(I) all: 0.585 / Net I/σ(I): 5.2 / Num. measured all: 1069191
Reflection shellResolution: 2.19→2.23 Å / % possible obs: 98.8 % / Redundancy: 7.5 % / Rmerge(I) obs: 9.221 / Num. measured all: 38235 / Num. unique obs: 5066 / CC1/2: 0.205 / Rpim(I) all: 3.292 / Rrim(I) all: 9.814 / Net I/σ(I) obs: 0.5

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHENIX1.11.1_2575refinement
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.19→49.63 Å / SU ML: 0.34 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 31.12 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.251 10122 5.01 %random
Rwork0.1932 ---
obs0.1961 104300 99.81 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.19→49.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13571 0 378 670 14619
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00814420
X-RAY DIFFRACTIONf_angle_d0.95219635
X-RAY DIFFRACTIONf_dihedral_angle_d17.38421
X-RAY DIFFRACTIONf_chiral_restr0.0532025
X-RAY DIFFRACTIONf_plane_restr0.0062477
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1901-2.21490.36833530.31756237X-RAY DIFFRACTION98
2.2149-2.2410.39743290.32666430X-RAY DIFFRACTION100
2.241-2.26830.44153420.36596443X-RAY DIFFRACTION100
2.2683-2.2970.36843120.31626277X-RAY DIFFRACTION100
2.297-2.32730.35413290.30956568X-RAY DIFFRACTION100
2.3273-2.35920.36583660.30446344X-RAY DIFFRACTION100
2.3592-2.39290.37363150.29336391X-RAY DIFFRACTION100
2.3929-2.42860.333620.28686308X-RAY DIFFRACTION100
2.4286-2.46650.39433320.30366550X-RAY DIFFRACTION100
2.4665-2.5070.32483570.28016302X-RAY DIFFRACTION100
2.507-2.55020.2973480.26746373X-RAY DIFFRACTION100
2.5502-2.59660.30283460.2556452X-RAY DIFFRACTION100
2.5966-2.64650.30473650.2526298X-RAY DIFFRACTION100
2.6465-2.70050.30373480.25946413X-RAY DIFFRACTION100
2.7005-2.75920.33223380.26386499X-RAY DIFFRACTION100
2.7592-2.82340.32082810.24066404X-RAY DIFFRACTION100
2.8234-2.8940.29682910.23146502X-RAY DIFFRACTION100
2.894-2.97220.28893720.22766265X-RAY DIFFRACTION100
2.9722-3.05970.31083180.22416507X-RAY DIFFRACTION100
3.0597-3.15840.29743260.21646381X-RAY DIFFRACTION100
3.1584-3.27130.26873400.20766435X-RAY DIFFRACTION100
3.2713-3.40220.24983350.18056349X-RAY DIFFRACTION100
3.4022-3.5570.22283410.17116424X-RAY DIFFRACTION100
3.557-3.74450.22743430.166472X-RAY DIFFRACTION100
3.7445-3.9790.21593640.14966354X-RAY DIFFRACTION100
3.979-4.28610.16623050.13136430X-RAY DIFFRACTION100
4.2861-4.71710.18982990.12556461X-RAY DIFFRACTION100
4.7171-5.3990.17554030.13076343X-RAY DIFFRACTION100
5.399-6.79940.20043260.15346419X-RAY DIFFRACTION100
6.7994-49.630.20683360.14836403X-RAY DIFFRACTION100
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)
10.8519-0.22050.1020.52820.25411.9386-0.0308-0.0439-0.0456-0.00290.01280.04780.1432-0.00090.01710.3015-0.00530.0520.2580.05850.3031-34.40377.7554-38.5475
20.9633-0.1642-0.0580.53010.07812.789-0.07460.0350.05750.07130.0324-0.0115-0.11140.09220.04410.3519-0.0106-0.00330.26390.03260.297-34.69.7614-0.9578
30.96090.13760.03550.63040.0422.905-0.0738-0.0265-0.0707-0.06950.0212-0.00640.12520.07460.04560.30340.00450.00890.2250.03080.273324.577631.4957-81.3961
40.73460.1477-0.00640.48870.23241.9635-0.03350.040.02810.01940.00690.0485-0.1003-0.01170.02450.26080.002-0.03840.22260.05070.281224.793433.5236-43.8498
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 304:722)
2X-RAY DIFFRACTION2(chain B and resid 305:722)
3X-RAY DIFFRACTION3(chain C and resid 304:722)
4X-RAY DIFFRACTION4(chain D and resid 304:722)

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