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- PDB-6auw: Structure of rat neuronal nitric oxide synthase heme domain in co... -

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Basic information

Entry
Database: PDB / ID: 6auw
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with 4-Methyl-6-(2-(5-(4-((methylamino)methyl)phenyl)pyridin-3-yl)ethyl)pyridin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/inhibitor / nitric oxide synthase inhibitor heme enzyme / OXIDOREDUCTASE / OXIDOREDUCTASE-inhibitor complex
Function / homology
Function and homology information


negative regulation of hepatic stellate cell contraction / Nitric oxide stimulates guanylate cyclase / positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / negative regulation of iron ion transmembrane transport / response to vitamin B3 / postsynaptic specialization, intracellular component / ROS and RNS production in phagocytes / azurophil granule / synaptic signaling by nitric oxide / Ion homeostasis ...negative regulation of hepatic stellate cell contraction / Nitric oxide stimulates guanylate cyclase / positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / negative regulation of iron ion transmembrane transport / response to vitamin B3 / postsynaptic specialization, intracellular component / ROS and RNS production in phagocytes / azurophil granule / synaptic signaling by nitric oxide / Ion homeostasis / negative regulation of vasoconstriction / response to nitric oxide / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of cytosolic calcium ion concentration / response to vitamin E / 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 / regulation of neurogenesis / negative regulation of serotonin uptake / nitric-oxide synthase activity / multicellular organismal response to stress / xenobiotic catabolic process / L-arginine catabolic process / postsynaptic density, intracellular component / NADPH binding / striated muscle contraction / nitric oxide-cGMP-mediated signaling / regulation of sodium ion transport / negative regulation of blood pressure / response to hormone / behavioral response to cocaine / nitric oxide metabolic process / nitric oxide biosynthetic process / photoreceptor inner segment / T-tubule / cellular response to epinephrine stimulus / sarcoplasmic reticulum membrane / secretory granule / calyx of Held / sarcoplasmic reticulum / positive regulation of long-term synaptic potentiation / response to activity / cell periphery / response to nicotine / response to nutrient levels / phosphoprotein binding / establishment of protein localization / establishment of localization in cell / cellular response to mechanical stimulus / female pregnancy / negative regulation of insulin secretion / response to peptide hormone / sarcolemma / caveola / cellular response to growth factor stimulus / potassium ion transport / response to lead ion / response to estrogen / vasodilation / Z disc / calcium-dependent protein binding / calcium ion transport / FMN binding / NADP binding / flavin adenine dinucleotide binding / positive regulation of neuron apoptotic process / response to heat / ATPase binding / scaffold protein binding / response to ethanol / nuclear membrane / response to lipopolysaccharide / dendritic spine / negative regulation of neuron apoptotic process / RNA polymerase II-specific DNA-binding transcription factor binding / transmembrane transporter binding / mitochondrial outer membrane / cytoskeleton / calmodulin binding / response to hypoxia / postsynaptic density / membrane raft / negative regulation of cell population proliferation / heme binding / synapse / dendrite / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / glutamatergic synapse / enzyme binding / positive regulation of transcription by RNA polymerase II
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, N-terminal / Nitric oxide synthase, N-terminal domain superfamily / Nitric oxide synthase, domain 2 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, 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 / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
ACETATE ION / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-W80 / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.7 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: J. Med. Chem. / Year: 2017
Title: Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker.
Authors: Do, H.T. / Wang, H.Y. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionSep 1, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 11, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,18911
Polymers97,6252
Non-polymers2,5649
Water7,116395
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9830 Å2
ΔGint-85 kcal/mol
Surface area33020 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.915, 111.071, 164.021
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 / BNOS / Constitutive NOS / NC-NOS / NOS type I / Neuronal NOS / nNOS / Peptidyl-cysteine S-nitrosylase NOS1


Mass: 48812.527 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Residues 339 to 349 are disordered. The N-terminal residues 297 and 298 as well as C-terminal residues 717 and 718 are not observed in density
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Nos1, Bnos / Organ: brain / Plasmid: pCWori / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P29476, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 404 molecules

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


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


Mass: 241.247 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H15N5O3
#4: Chemical ChemComp-W80 / 4-methyl-6-[2-(5-{4-[(methylamino)methyl]phenyl}pyridin-3-yl)ethyl]pyridin-2-amine


Mass: 332.442 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H24N4
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#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


Mass: 18.015 Da / Num. of mol.: 395 / 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: 2.48 Å3/Da / Density % sol: 50.4 % / Description: bricks
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.8
Details: 20-24% PEG3350, 0.1M MES 0.14-0.20M AMMONIUM ACETATE, 10% ETHYLENE GLYCOL, 30uM SDS, 5 mM GSH

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.9794 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 19, 2016 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9794 Å / Relative weight: 1
ReflectionResolution: 1.7→55 Å / Num. obs: 104763 / % possible obs: 99.3 % / Observed criterion σ(I): -3 / Redundancy: 5.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.034 / Rsym value: 0.077 / Net I/σ(I): 11.2
Reflection shellResolution: 1.7→1.74 Å / Redundancy: 5.5 % / Rmerge(I) obs: 4.251 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 4968 / CC1/2: 0.558 / Rpim(I) all: 1.924 / Rsym value: 4.251 / % possible all: 99.3

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 1OM4

1om4


Resolution: 1.7→38.961 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 0.92 / Phase error: 34.39
RfactorNum. reflection% reflectionSelection details
Rfree0.2291 5065 4.99 %random
Rwork0.1942 ---
obs0.196 101560 95.97 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.7→38.961 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6659 0 179 395 7233
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077088
X-RAY DIFFRACTIONf_angle_d1.1129647
X-RAY DIFFRACTIONf_dihedral_angle_d14.5842576
X-RAY DIFFRACTIONf_chiral_restr0.039996
X-RAY DIFFRACTIONf_plane_restr0.0051219
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6988-1.71810.50071520.52123609X-RAY DIFFRACTION55
1.7181-1.73830.47213000.49395528X-RAY DIFFRACTION86
1.7383-1.75950.45392770.45375488X-RAY DIFFRACTION87
1.7595-1.78180.45863210.44765718X-RAY DIFFRACTION89
1.7818-1.80530.42953430.43785837X-RAY DIFFRACTION92
1.8053-1.830.46463390.4036072X-RAY DIFFRACTION95
1.83-1.85610.40413620.39956353X-RAY DIFFRACTION99
1.8561-1.88380.44453030.376345X-RAY DIFFRACTION99
1.8838-1.91330.4213030.35976382X-RAY DIFFRACTION99
1.9133-1.94460.38123510.33526304X-RAY DIFFRACTION99
1.9446-1.97820.34763850.30656262X-RAY DIFFRACTION99
1.9782-2.01420.34722940.29346341X-RAY DIFFRACTION99
2.0142-2.05290.31923270.2796345X-RAY DIFFRACTION99
2.0529-2.09480.32523300.2616296X-RAY DIFFRACTION99
2.0948-2.14030.3382630.24656333X-RAY DIFFRACTION98
2.1403-2.19010.32552950.24046282X-RAY DIFFRACTION97
2.1901-2.24490.30143310.22736328X-RAY DIFFRACTION99
2.2449-2.30560.29043910.21636303X-RAY DIFFRACTION99
2.3056-2.37340.23753250.20066360X-RAY DIFFRACTION99
2.3734-2.450.2823360.21136416X-RAY DIFFRACTION100
2.45-2.53760.27853160.20246364X-RAY DIFFRACTION100
2.5376-2.63910.23513420.18646340X-RAY DIFFRACTION99
2.6391-2.75920.21653110.19266375X-RAY DIFFRACTION99
2.7592-2.90460.24093270.18786352X-RAY DIFFRACTION99
2.9046-3.08660.23583700.19536354X-RAY DIFFRACTION100
3.0866-3.32480.23363090.17536370X-RAY DIFFRACTION100
3.3248-3.65910.16513470.15536372X-RAY DIFFRACTION100
3.6591-4.18810.17793340.13376299X-RAY DIFFRACTION99
4.1881-5.27440.15833820.1286307X-RAY DIFFRACTION99
5.2744-38.97150.14463140.14576207X-RAY DIFFRACTION97
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)
10.945-0.1173-0.62011.2251-0.26947.7356-0.05530.15-0.03430.0239-0.06760.07250.2582-0.45650.05730.2902-0.02630.00890.2559-0.01280.265611.35394.755222.4352
20.8368-0.1153-0.1181.10530.34663.334-0.00170.01850.022-0.2014-0.0694-0.04240.24270.12870.05150.25360.02350.03420.21320.01620.236912.25584.801359.6632
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 299:716)
2X-RAY DIFFRACTION2(chain B and resid 299:718)

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