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- PDB-7ts2: Structure of human neuronal nitric oxide synthase R354A/G357D mut... -

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Basic information

Entry
Database: PDB / ID: 7ts2
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 6-(3-(3,3-difluoroazetidin-1-yl)propyl)-4-methylpyridin-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 / negative regulation of hydrolase activity / tetrahydrobiopterin binding / regulation of cardiac muscle contraction by calcium ion signaling / arginine binding / 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 / Nitric oxide stimulates guanylate cyclase / myoblast fusion / ROS and RNS production in phagocytes / negative regulation of hydrolase activity / tetrahydrobiopterin binding / regulation of cardiac muscle contraction by calcium ion signaling / arginine binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / positive regulation of sodium ion transmembrane transport / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / peptidyl-cysteine S-nitrosylation / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of potassium ion transport / negative regulation of calcium ion transport / regulation of cardiac muscle contraction / negative regulation of serotonin uptake / calcium channel regulator activity / nitric-oxide synthase (NADPH) / sodium channel regulator activity / regulation of ryanodine-sensitive calcium-release channel activity / nitric oxide mediated signal transduction / nitric-oxide synthase activity / xenobiotic catabolic process / multicellular organismal response to stress / arginine catabolic process / striated muscle contraction / regulation of sodium ion transport / Ion homeostasis / nitric oxide biosynthetic process / negative regulation of blood pressure / photoreceptor inner segment / response to hormone / cell redox homeostasis / sarcoplasmic reticulum / cell periphery / sarcolemma / cellular response to growth factor stimulus / vasodilation / calcium-dependent protein binding / FMN binding / positive regulation of peptidyl-serine phosphorylation / flavin adenine dinucleotide binding / NADP binding / response to heat / scaffold protein binding / transmembrane transporter binding / response to lipopolysaccharide / dendritic spine / postsynaptic density / cytoskeleton / calmodulin binding / response to hypoxia / 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 / 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 / Chem-K8F / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.9758 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 1.1Dec 21, 2022Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name
Revision 1.2Oct 25, 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

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)201,06724
Polymers195,9874
Non-polymers5,07920
Water20,7531152
1
A: Nitric oxide synthase, brain
B: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,53312
Polymers97,9942
Non-polymers2,54010
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9800 Å2
ΔGint-81 kcal/mol
Surface area34580 Å2
MethodPISA
2
C: Nitric oxide synthase, brain
D: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,53312
Polymers97,9942
Non-polymers2,54010
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9940 Å2
ΔGint-81 kcal/mol
Surface area34240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.319, 118.679, 164.995
Angle α, β, γ (deg.)90.000, 90.130, 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 / N-NOS / nNOS / Peptidyl-cysteine S- ...Constitutive NOS / NC-NOS / NOS type I / Neuronal NOS / N-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, 1172 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-K8F / 6-[3-(3,3-difluoroazetidin-1-yl)propyl]-4-methylpyridin-2-amine


Mass: 241.280 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C12H17F2N3 / 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.: 1152 / 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: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 26, 2021 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.9758→39.56 Å / Num. obs: 139658 / % possible obs: 99.1 % / Redundancy: 9.5 % / Biso Wilson estimate: 29.04 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.231 / Rpim(I) all: 0.077 / Rrim(I) all: 0.244 / Net I/σ(I): 8.4
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
1.9758-2.015.12.0283074160600.4380.9892.2660.885.8
10.82-39.56110.06996278780.9980.0220.07229.298

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Processing

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

4uh5


Resolution: 1.9758→38.9699 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 0.02 / Phase error: 26.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2298 13885 5.04 %random
Rwork0.1819 261572 --
obs0.1843 139479 99.01 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 136.21 Å2 / Biso mean: 40.3938 Å2 / Biso min: 15.63 Å2
Refinement stepCycle: final / Resolution: 1.9758→38.9699 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13575 0 346 1152 15073
Biso mean--41.73 43.22 -
Num. residues----1665
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00714416
X-RAY DIFFRACTIONf_angle_d1.09819635
X-RAY DIFFRACTIONf_chiral_restr0.0542038
X-RAY DIFFRACTIONf_plane_restr0.0062478
X-RAY DIFFRACTIONf_dihedral_angle_d17.7798449
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 (%)
1.9758-1.99830.36724280.3127055748380
1.9983-2.02180.35555060.30118656916298
2.0218-2.04640.30394720.28398501897398
2.0464-2.07230.36894260.31328758918498
2.0723-2.09960.31674260.29458728915499
2.0996-2.12830.28944700.266187189188100
2.1283-2.15870.34024990.273988449343100
2.1587-2.1910.33874800.27488199299100
2.191-2.22520.32214300.254886719101100
2.2252-2.26170.31024840.268188289312100
2.2617-2.30070.30874770.237987259202100
2.3007-2.34250.27925060.222686929198100
2.3425-2.38760.2514690.215789089377100
2.3876-2.43630.27644490.214187359184100
2.4363-2.48920.26024750.213288969371100
2.4892-2.54710.244620.194587009162100
2.5471-2.61080.26125050.186488529357100
2.6108-2.68140.24164590.191486809139100
2.6814-2.76030.25584380.198789989436100
2.7603-2.84940.25744670.18586559122100
2.8494-2.95120.20954150.173989019316100
2.9512-3.06930.24264340.179788699303100
3.0693-3.20890.2524340.18587919225100
3.2089-3.3780.23215160.165287599275100
3.378-3.58950.20224750.153888059280100
3.5895-3.86640.1874790.147187509229100
3.8664-4.25510.16844680.13688059273100
4.2551-4.86980.15024420.122788469288100
4.8698-6.13160.18854540.143288209274100
6.1316-38.96990.18974400.158188079247100
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)
10.5762-0.19-0.0810.692-0.21162.79640.02650.06090.02240.0507-0.0639-0.0839-0.06110.09080.02850.1772-0.0052-0.03520.1785-0.0020.1784-10.899-4.746-40.169
20.4533-0.1627-0.16330.8976-0.14241.69450.0120.0109-0.0545-0.057-0.01190.0449-0.0273-0.0605-0.00250.1624-0.0168-0.04320.206-0.03640.2311-12.854-4.32-2.695
30.42780.11730.21730.7792-0.06231.61330.0274-0.00170.06110.0649-0.03240.0510.0379-0.0674-0.00080.16350.00620.04790.1992-0.03850.229213.49-54.358-79.763
40.43390.22540.01360.6101-0.14542.74210.02-0.0569-0.0216-0.0303-0.063-0.09380.04790.08150.03760.20910.00430.03830.22760.00060.221615.306-53.956-42.231
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 303:722 )A303 - 722
2X-RAY DIFFRACTION2( CHAIN B AND RESID 304:722 )B304 - 722
3X-RAY DIFFRACTION3( CHAIN C AND RESID 303:722 )C303 - 722
4X-RAY DIFFRACTION4( CHAIN D AND RESID 305:722 )D305 - 722

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