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- PDB-7ts1: Structure of human neuronal nitric oxide synthase R354A/G357D mut... -

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Basic information

Entry
Database: PDB / ID: 7ts1
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 6-(3-(4,4-difluoropiperidin-1-yl)prop-1-yn-1-yl)-4-methylpyridin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor / heme enzyme
Function / homology
Function and homology information


negative regulation of calcium ion transport into cytosol / myoblast fusion / Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / negative regulation of hydrolase activity / tetrahydrobiopterin binding / arginine binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / retrograde trans-synaptic signaling by nitric oxide / positive regulation of sodium ion transmembrane transport ...negative regulation of calcium ion transport into cytosol / myoblast fusion / Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / negative regulation of hydrolase activity / tetrahydrobiopterin binding / arginine binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / retrograde trans-synaptic signaling by nitric oxide / 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 / negative regulation of serotonin uptake / sodium channel regulator activity / striated muscle contraction / nitric-oxide synthase (NADPH) / regulation of cardiac muscle contraction / multicellular organismal response to stress / xenobiotic catabolic process / nitric-oxide synthase activity / nitric oxide mediated signal transduction / arginine catabolic process / regulation of sodium ion transport / regulation of ryanodine-sensitive calcium-release channel activity / Ion homeostasis / photoreceptor inner segment / nitric oxide biosynthetic process / negative regulation of blood pressure / response to hormone / cell redox homeostasis / sarcoplasmic reticulum / muscle contraction / cell periphery / sarcolemma / cellular response to growth factor stimulus / vasodilation / calcium-dependent protein binding / FMN binding / flavin adenine dinucleotide binding / positive regulation of peptidyl-serine phosphorylation / NADP binding / response to heat / scaffold protein binding / transmembrane transporter binding / response to lipopolysaccharide / dendritic spine / postsynaptic density / response to hypoxia / cytoskeleton / calmodulin binding / membrane raft / synapse / heme binding / perinuclear region of cytoplasm / positive regulation of DNA-templated transcription / 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, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain 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 ...Nitric-oxide synthase, eukaryote / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain 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-K8O / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.06 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)201,16324
Polymers195,9874
Non-polymers5,17620
Water11,602644
1
A: Nitric oxide synthase, brain
B: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,48911
Polymers97,9942
Non-polymers2,4969
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9990 Å2
ΔGint-85 kcal/mol
Surface area33310 Å2
MethodPISA
2
C: Nitric oxide synthase, brain
D: Nitric oxide synthase, brain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,67313
Polymers97,9942
Non-polymers2,68011
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9890 Å2
ΔGint-82 kcal/mol
Surface area32750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.548, 162.872, 117.133
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, 664 molecules

#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN / Tetrahydrobiopterin


Mass: 241.247 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#4: Chemical
ChemComp-K8O / 6-[3-(4,4-difluoropiperidin-1-yl)prop-1-yn-1-yl]-4-methylpyridin-2-amine


Mass: 265.302 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H17F2N3 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


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 / Water


Mass: 18.015 Da / Num. of mol.: 644 / 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: 5.0.2 / Wavelength: 0.9845 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 10, 2021 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9845 Å / Relative weight: 1
ReflectionResolution: 2.06→49.271 Å / Num. obs: 118887 / % possible obs: 100 % / Redundancy: 4.6 % / Biso Wilson estimate: 34.87 Å2 / CC1/2: 0.976 / Rmerge(I) obs: 0.264 / Rpim(I) all: 0.135 / Rrim(I) all: 0.298 / Net I/σ(I): 2.9
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
2.06-2.14.53.7712609958380.1231.9714.2710.4100
11.28-49.264.90.07136797520.9090.0380.0818.399.1

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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: 2.06→49.271 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 32.21 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2567 11699 5.03 %random
Rwork0.202 221025 --
obs0.2048 117789 98.82 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 130.02 Å2 / Biso mean: 49.7574 Å2 / Biso min: 21.21 Å2
Refinement stepCycle: final / Resolution: 2.06→49.271 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13557 0 354 644 14555
Biso mean--46.55 46.6 -
Num. residues----1663
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00814382
X-RAY DIFFRACTIONf_angle_d0.97519578
X-RAY DIFFRACTIONf_chiral_restr0.0522028
X-RAY DIFFRACTIONf_plane_restr0.0062470
X-RAY DIFFRACTIONf_dihedral_angle_d18.0798422
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 (%)
2.06-2.08340.40723530.35176718707191
2.0834-2.10790.3873800.32726851723193
2.1079-2.13360.40213650.31987145751094
2.1336-2.16060.35063600.29547100746096
2.1606-2.18910.34993670.29277121748897
2.1891-2.21910.35914210.31277301772298
2.2191-2.25080.37624270.30117483791099
2.2508-2.28440.34724140.27973677781100
2.2844-2.320.32163620.274974317793100
2.32-2.35810.3454450.268574287873100
2.3581-2.39870.33184100.264574277837100
2.3987-2.44240.33723960.271375357931100
2.4424-2.48930.31863650.253173427707100
2.4893-2.54010.3174480.253973757823100
2.5401-2.59540.28944030.24567550795399
2.5954-2.65570.29453470.245774287775100
2.6557-2.72220.32994160.251775077923100
2.7222-2.79570.26913820.227473707752100
2.7957-2.8780.28773890.221974987887100
2.878-2.97090.28724190.227773497768100
2.9709-3.07710.28844110.227774967907100
3.0771-3.20020.27853990.207175027901100
3.2002-3.34590.24373280.201574567784100
3.3459-3.52220.24024160.18474187834100
3.5222-3.74280.21693700.167774737843100
3.7428-4.03170.22164050.165674767881100
4.0317-4.43720.17923660.144974347800100
4.4372-5.07870.17493850.134975337918100
5.0787-6.39640.20244150.152874427857100
6.3964-49.2710.20773350.161674697804100
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)
10.50660.0011-0.16163.04920.12390.79640.0118-0.00070.0798-0.0170.0255-0.11190.02520.066-0.04140.29230.0216-0.01450.28690.0080.3372259.827349.778-63.684
20.61690.1819-0.10451.84420.0440.73780.03850.07230.01740.03220.0070.1006-0.0759-0.0588-0.05420.24010.0393-0.00240.27520.03580.2383257.928312.792-63.18
30.55310.02280.12823.02920.08050.78660.0238-0.0094-0.07530.02440.0292-0.0735-0.01010.0741-0.05750.2411-0.0284-0.00580.2689-0.00280.3089234.121351.702-112.201
40.6523-0.25250.15161.910.08440.89030.0294-0.0503-0.0186-0.0403-0.00920.16210.0628-0.0497-0.02260.22-0.0441-0.00220.30380.04040.2941232.137388.832-112.531
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 302:722 )A302 - 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 304:722 )D304 - 722

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