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- PDB-6ng6: Structure of human neuronal nitric oxide synthase R354A/G357D mut... -

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Basic information

Entry
Database: PDB / ID: 6ng6
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with (S)-6-(3-fluoro-5-(2-(pyrrolidin-2-yl)ethyl)phenethyl)-4-methylpyridin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / nitric oxide synthase / inhibitor complex / heme enzyme / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / 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 / negative regulation of blood pressure / nitric oxide biosynthetic process / response to hormone / cell redox homeostasis / muscle contraction / sarcoplasmic reticulum / 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 / calmodulin binding / cytoskeleton / 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
Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / Nitric-oxide synthase, eukaryote / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily ...Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / 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 / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-KL4 / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.044 Å
AuthorsLi, H. / Poulos, T.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)GM57353 United States
CitationJournal: J. Med. Chem. / Year: 2019
Title: Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold.
Authors: Do, H.T. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionDec 21, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,09710
Polymers97,5692
Non-polymers2,5288
Water6,449358
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9610 Å2
ΔGint-85 kcal/mol
Surface area33280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.118, 121.389, 164.168
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Nitric oxide synthase, brain / / Constitutive NOS / NC-NOS / NOS type I / Neuronal NOS / nNOS / Peptidyl-cysteine S-nitrosylase NOS1 / bNOS


Mass: 48784.496 Da / Num. of mol.: 2 / Fragment: UNP residues 302-722 / 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, 366 molecules

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


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN / Tetrahydrobiopterin


Mass: 241.247 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#4: Chemical ChemComp-KL4 / 6-[2-(3-fluoro-5-{2-[(2S)-pyrrolidin-2-yl]ethyl}phenyl)ethyl]-4-methylpyridin-2-amine


Mass: 327.439 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H26FN3
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 358 / Source method: isolated from a natural source / Formula: H2O

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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, 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 315r / Detector: CCD / Date: Apr 15, 2017 / Details: mirrors
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.044→60 Å / Num. obs: 65325 / % possible obs: 98.3 % / Observed criterion σ(I): -3 / Redundancy: 10.4 % / CC1/2: 0.99 / Rmerge(I) obs: 0.2 / Rpim(I) all: 0.063 / Rsym value: 0.2 / Net I/σ(I): 6
Reflection shellResolution: 2.04→2.12 Å / Redundancy: 8.6 % / Rmerge(I) obs: 1.893 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 4344 / CC1/2: 0.259 / Rpim(I) all: 0.667 / Rsym value: 1.893 / % possible all: 93.2

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Processing

Software
NameVersionClassification
PHENIX(1.11.1-2575_1496: ???)refinement
MOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 5AD7

5ad7


Resolution: 2.044→49.888 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 26.26
RfactorNum. reflection% reflectionSelection details
Rfree0.2296 6099 4.89 %random
Rwork0.1847 ---
obs0.1869 65107 97.96 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.044→49.888 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6693 0 175 358 7226
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077114
X-RAY DIFFRACTIONf_angle_d0.9819688
X-RAY DIFFRACTIONf_dihedral_angle_d18.064161
X-RAY DIFFRACTIONf_chiral_restr0.0511001
X-RAY DIFFRACTIONf_plane_restr0.0061223
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0442-2.06740.39341990.34163525X-RAY DIFFRACTION87
2.0674-2.09180.32262140.30933976X-RAY DIFFRACTION98
2.0918-2.11730.33152140.28113869X-RAY DIFFRACTION99
2.1173-2.14410.31612090.26694046X-RAY DIFFRACTION98
2.1441-2.17230.30671870.26424030X-RAY DIFFRACTION98
2.1723-2.2020.32891840.27813971X-RAY DIFFRACTION99
2.202-2.23350.38332090.31793919X-RAY DIFFRACTION98
2.2335-2.26680.4031860.38254025X-RAY DIFFRACTION97
2.2668-2.30230.38991980.27423892X-RAY DIFFRACTION99
2.3023-2.340.27432180.21934034X-RAY DIFFRACTION99
2.34-2.38040.28192300.21553946X-RAY DIFFRACTION99
2.3804-2.42360.2662150.20553977X-RAY DIFFRACTION99
2.4236-2.47030.26912270.2134014X-RAY DIFFRACTION99
2.4703-2.52070.23382230.2023935X-RAY DIFFRACTION99
2.5207-2.57550.2432020.1914035X-RAY DIFFRACTION99
2.5755-2.63540.26092180.18963999X-RAY DIFFRACTION99
2.6354-2.70130.23012200.20084000X-RAY DIFFRACTION99
2.7013-2.77430.22351780.18853969X-RAY DIFFRACTION99
2.7743-2.8560.24931820.18964045X-RAY DIFFRACTION99
2.856-2.94810.24652050.19584011X-RAY DIFFRACTION99
2.9481-3.05350.27421930.19264038X-RAY DIFFRACTION99
3.0535-3.17570.232030.19193944X-RAY DIFFRACTION99
3.1757-3.32020.25162080.17633970X-RAY DIFFRACTION98
3.3202-3.49520.221820.17794006X-RAY DIFFRACTION98
3.4952-3.71410.20032200.16283932X-RAY DIFFRACTION98
3.7141-4.00080.19962070.15523929X-RAY DIFFRACTION97
4.0008-4.40320.17352100.13873880X-RAY DIFFRACTION97
4.4032-5.03980.15891920.13323943X-RAY DIFFRACTION98
5.0398-6.34760.19011930.15763955X-RAY DIFFRACTION97
6.3476-49.90260.19561730.1543847X-RAY DIFFRACTION95
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)
10.9107-0.2833-0.02091.10060.31652.37190.0348-0.00440.0057-0.0884-0.087-0.0780.13360.16010.04890.2127-0.01880.03760.26240.05180.2652117.0827247.8061359.0556
20.8636-0.391-0.01141.07320.11574.13170.06240.0839-0.0422-0.0364-0.0820.12450.0517-0.23710.00620.24580.00090.0420.3028-0.04610.2811115.6262246.3463321.8902
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)

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