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- PDB-7ts8: Structure of human neuronal nitric oxide synthase R354A/G357D mut... -

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Basic information

Entry
Database: PDB / ID: 7ts8
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 4-chloro-6-((5-(2-(dimethylamino)ethyl)-2,3-difluorophenyl)ethynyl)pyridin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor / heme enzyme
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 / Chem-KL0 / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 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)GM57353 United States
CitationJournal: Bioorg.Med.Chem. / Year: 2022
Title: 2-Aminopyridines with a shortened amino sidechain as potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors.
Authors: Vasu, D. / Li, H. / Hardy, C.D. / Poulos, T.L. / Silverman, R.B.
History
DepositionJan 31, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 13, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)200,87524
Polymers195,9874
Non-polymers4,88720
Water7,242402
1
A: Nitric oxide synthase, brain
B: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,43712
Polymers97,9942
Non-polymers2,44410
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10060 Å2
ΔGint-120 kcal/mol
Surface area33600 Å2
MethodPISA
2
C: Nitric oxide synthase, brain
D: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,43712
Polymers97,9942
Non-polymers2,44410
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10070 Å2
ΔGint-121 kcal/mol
Surface area33860 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.910, 163.780, 118.239
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: pCWori / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P29475, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 422 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-KL0 / 6-[3-(dimethylamino)propyl]-4-methylpyridin-2-amine


Mass: 193.289 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C11H19N3 / 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.: 402 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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 35mM citric acid 65mM Bis-Tris-Propane 10% glycerol 5mM 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: Apr 17, 2021 / 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: 2.3→67.3496 Å / Num. obs: 87439 / % possible obs: 100 % / Redundancy: 3.7 % / Biso Wilson estimate: 36.27 Å2 / CC1/2: 0.965 / Rmerge(I) obs: 0.319 / Rpim(I) all: 0.188 / Rrim(I) all: 0.372 / Net I/σ(I): 3.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.3-2.343.63.0781631044850.2361.7673.5610.699.9
12.39-67.323.70.05421975920.9730.0350.06512.299.5

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Processing

Software
NameVersionClassification
Aimless0.2.8data scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.27data extraction
MOSFLMdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4UH5

4uh5


Resolution: 2.3→67.3496 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 34.34 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2831 8485 4.92 %random
Rwork0.2191 164063 --
obs0.2223 87244 99.73 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 155 Å2 / Biso mean: 52.7751 Å2 / Biso min: 18.46 Å2
Refinement stepCycle: final / Resolution: 2.3→67.3496 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13445 0 334 402 14181
Biso mean--48.48 44.42 -
Num. residues----1650
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00814242
X-RAY DIFFRACTIONf_angle_d1.04219379
X-RAY DIFFRACTIONf_chiral_restr0.0532013
X-RAY DIFFRACTIONf_plane_restr0.0062444
X-RAY DIFFRACTIONf_dihedral_angle_d18.3368320
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.3-2.32620.40642890.31165329561899
2.3262-2.35350.39852390.313456815920100
2.3535-2.38220.41022850.30754235708100
2.3822-2.41240.37873200.305153765696100
2.4124-2.44410.38352960.308155315827100
2.4441-2.47760.36122930.310255095802100
2.4776-2.5130.38493060.305653705676100
2.513-2.55050.37242660.297955405806100
2.5505-2.59040.3513140.277154715785100
2.5904-2.63290.37212610.291154575718100
2.6329-2.67830.38272500.310354185668100
2.6783-2.7270.36482750.311255665841100
2.727-2.77940.37642730.291354455718100
2.7794-2.83610.28922600.270354995759100
2.8361-2.89780.33153410.263754655806100
2.8978-2.96520.32192760.269754575733100
2.9652-3.03940.36572640.27255285792100
3.0394-3.12160.34562650.265554405705100
3.1216-3.21340.32382980.245655425840100
3.2134-3.31710.25452800.222254845764100
3.3171-3.43570.27462730.22254905763100
3.4357-3.57320.27773020.209554365738100
3.5732-3.73580.32452690.24155398566797
3.7358-3.93280.25032990.20495383568299
3.9328-4.17920.21132820.16154395721100
4.1792-4.50180.20892950.152454305725100
4.5018-4.95470.22662690.139355475816100
4.9547-5.67130.23432880.160354795767100
5.6713-7.1440.22282710.16155035774100
7.144-67.34960.19412860.1615427571399
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)
10.750.0646-0.15444.14520.07731.2412-0.03490.01490.1719-0.09110.07140.0204-0.03180.096-0.02980.25890.0226-0.01230.29810.00020.3778261.489351.897-63.812
20.84810.1047-0.18862.40110.24841.0006-0.00270.06360.00660.05240.00260.0972-0.0617-0.05420.00060.24020.0496-0.02880.27140.04750.2763259.801314.679-63.616
30.8206-0.01780.17944.1049-0.12571.21670.0042-0.0107-0.09360.07590.0406-0.0040.04280.0612-0.04190.2552-0.02050.02650.2727-0.00360.3751235.565353.454-113.623
40.8144-0.28890.07882.29070.21220.83450.0032-0.0667-0.0169-0.0251-0.00890.10290.07-0.0534-0.0020.2262-0.05370.02620.27260.05480.2591233.765390.787-113.643
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 304:722 )A304 - 722
2X-RAY DIFFRACTION2( CHAIN B AND RESID 304:722 )B304 - 722
3X-RAY DIFFRACTION3( CHAIN C AND RESID 305:722 )C305 - 722
4X-RAY DIFFRACTION4( CHAIN D AND RESID 304:724 )D304 - 724

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