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- PDB-9cw1: Structure of human neuronal nitric oxide synthase R354A/G357D mut... -

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Basic information

Entry
Database: PDB / ID: 9cw1
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain bound with 6-(2,3-difluoro-5-(2-(methylamino)ethyl)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 / 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: 1.9 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

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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)201,21124
Polymers195,9874
Non-polymers5,22420
Water22,7531263
1
A: Nitric oxide synthase, brain
B: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,60512
Polymers97,9942
Non-polymers2,61210
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9710 Å2
ΔGint-80 kcal/mol
Surface area33250 Å2
MethodPISA
2
C: Nitric oxide synthase, brain
D: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,60512
Polymers97,9942
Non-polymers2,61210
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9860 Å2
ΔGint-80 kcal/mol
Surface area33140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.562, 116.068, 163.034
Angle α, β, γ (deg.)90.00, 90.04, 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, 1283 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-A1A0C / (6M)-6-{2,3-difluoro-5-[2-(methylamino)ethyl]phenyl}-4-methylpyridin-2-amine


Mass: 277.312 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C15H17F2N3 / 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.: 1263 / 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: 2.49 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: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 24, 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: 1.9→49.15 Å / Num. obs: 150418 / % possible obs: 99.8 % / Redundancy: 3.3 % / CC1/2: 0.988 / Rmerge(I) obs: 0.118 / Rpim(I) all: 0.077 / Rrim(I) all: 0.142 / Net I/σ(I): 4.5 / Num. measured all: 494643
Reflection shellResolution: 1.9→1.93 Å / % possible obs: 99.8 % / Redundancy: 3.3 % / Rmerge(I) obs: 1.506 / Num. measured all: 24753 / Num. unique obs: 7402 / CC1/2: 0.341 / Rpim(I) all: 0.981 / Rrim(I) all: 1.804 / Net I/σ(I) obs: 0.8

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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: 1.9→49.15 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 0.66 / Phase error: 23.92 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2195 14572 5.07 %random
Rwork0.1751 ---
obs0.1773 149322 96.52 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.9→49.15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13558 0 358 1263 15179
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00714435
X-RAY DIFFRACTIONf_angle_d0.9519662
X-RAY DIFFRACTIONf_dihedral_angle_d17.4778436
X-RAY DIFFRACTIONf_chiral_restr0.0512030
X-RAY DIFFRACTIONf_plane_restr0.0062486
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.92160.38064470.36318156X-RAY DIFFRACTION86
1.9216-1.94420.38784730.3418642X-RAY DIFFRACTION93
1.9442-1.96790.37945370.33129074X-RAY DIFFRACTION96
1.9679-1.99280.29675470.29179189X-RAY DIFFRACTION98
1.9928-2.0190.2965090.26769080X-RAY DIFFRACTION98
2.019-2.04670.29344300.2699311X-RAY DIFFRACTION97
2.0467-2.07590.30614780.27129170X-RAY DIFFRACTION97
2.0759-2.10690.29335090.24879157X-RAY DIFFRACTION98
2.1069-2.13990.3064960.2489191X-RAY DIFFRACTION97
2.1399-2.17490.26624660.22619210X-RAY DIFFRACTION97
2.1749-2.21240.25175190.2169032X-RAY DIFFRACTION97
2.2124-2.25270.28684790.22399250X-RAY DIFFRACTION97
2.2527-2.2960.24445250.20739088X-RAY DIFFRACTION97
2.296-2.34290.2634770.20159254X-RAY DIFFRACTION97
2.3429-2.39380.22814890.18989026X-RAY DIFFRACTION97
2.3938-2.44950.22474860.18928931X-RAY DIFFRACTION94
2.4495-2.51070.23624600.18248783X-RAY DIFFRACTION94
2.5107-2.57860.23975280.17129224X-RAY DIFFRACTION97
2.5786-2.65450.23334860.18288816X-RAY DIFFRACTION95
2.6545-2.74020.22414370.18119243X-RAY DIFFRACTION98
2.7402-2.83810.22114990.1679310X-RAY DIFFRACTION98
2.8381-2.95170.19854500.16329252X-RAY DIFFRACTION98
2.9517-3.0860.24054510.16949377X-RAY DIFFRACTION98
3.086-3.24870.22344570.15649269X-RAY DIFFRACTION98
3.2487-3.45220.20285550.15219202X-RAY DIFFRACTION98
3.4522-3.71870.18084930.1359261X-RAY DIFFRACTION98
3.7187-4.09270.1685190.12879099X-RAY DIFFRACTION97
4.0927-4.68460.14694570.12088900X-RAY DIFFRACTION94
4.6846-5.90050.1844530.13529100X-RAY DIFFRACTION97
5.9005-49.150.17954600.1569339X-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)
10.4563-0.1293-0.07130.7470.02692.31690.02420.05840.00620.0149-0.0496-0.0677-0.05380.11130.0240.1675-0.0025-0.02370.19870.00140.1857-10.7921-4.3938-39.8062
20.4925-0.11-0.12360.60990.03011.38250.0156-0.0284-0.0321-0.0246-0.01940.0227-0.0307-0.0060.0040.2181-0.0152-0.0340.2049-0.02570.212-12.8273-4.129-2.6812
30.45510.15130.12840.6819-0.0261.48080.01330.02230.02970.0268-0.01760.02690.0336-0.01590.00480.20850.00680.03880.2031-0.02550.216513.007-53.2-78.8151
40.40650.12130.04520.7882-0.02232.30680.0214-0.0639-0.0012-0.006-0.0426-0.04450.04570.12110.02390.16710.00420.02650.20910.00310.1914.9934-52.8861-41.7197
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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