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- PDB-5vv3: Structure of human neuronal nitric oxide synthase heme domain in ... -

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Basic information

Entry
Database: PDB / ID: 5vv3
TitleStructure of human neuronal nitric oxide synthase heme domain in complex with 4-(2-(((2-Aminoquinolin-7-yl)methyl)amino)ethyl)benzonitrile
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 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
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
5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-P94 / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.18 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: Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.
Authors: Pensa, A.V. / Cinelli, M.A. / Li, H. / Chreifi, G. / Mukherjee, P. / Roman, L.J. / Martasek, P. / Poulos, T.L. / Silverman, R.B.
History
DepositionMay 19, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 16, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Sep 20, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 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

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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)100,13911
Polymers97,5692
Non-polymers2,5709
Water5,585310
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9990 Å2
ΔGint-123 kcal/mol
Surface area33780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.322, 123.501, 165.197
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: 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 (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P29475, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 319 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-P94 / 4-(2-{[(2-aminoquinolin-7-yl)methyl]amino}ethyl)benzonitrile


Mass: 302.373 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H18N4
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / 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


Mass: 18.015 Da / Num. of mol.: 310 / 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: plate
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
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 1.087 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 4, 2015 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.087 Å / Relative weight: 1
ReflectionResolution: 2.18→83 Å / Num. obs: 56821 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 5.1 % / CC1/2: 0.997 / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.08 / Rsym value: 0.109 / Net I/σ(I): 8.5
Reflection shellResolution: 2.18→2.28 Å / Redundancy: 5.2 % / Rmerge(I) obs: 1.482 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 4586 / CC1/2: 0.455 / Rpim(I) all: 1.114 / Rsym value: 1.482 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
iMOSFLM7.1.0data reduction
Aimless0.3.11data scaling
REFMAC5.8.0049phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4UH5

4uh5


Resolution: 2.18→82.599 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 0.18 / Phase error: 27.92
RfactorNum. reflection% reflectionSelection details
Rfree0.2293 5247 4.87 %random
Rwork0.1804 ---
obs0.1828 56721 99.63 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.18→82.599 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6693 0 179 310 7182
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087120
X-RAY DIFFRACTIONf_angle_d1.1389692
X-RAY DIFFRACTIONf_dihedral_angle_d14.6772588
X-RAY DIFFRACTIONf_chiral_restr0.073998
X-RAY DIFFRACTIONf_plane_restr0.0051223
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.179-2.20370.4031490.3173110X-RAY DIFFRACTION91
2.2037-2.22970.36391590.31413395X-RAY DIFFRACTION100
2.2297-2.25690.3461890.30843452X-RAY DIFFRACTION100
2.2569-2.28540.37351590.29313496X-RAY DIFFRACTION100
2.2854-2.31550.37791780.29343395X-RAY DIFFRACTION100
2.3155-2.34720.32271560.27133393X-RAY DIFFRACTION100
2.3472-2.38080.29622010.26643472X-RAY DIFFRACTION100
2.3808-2.41630.31612040.25043319X-RAY DIFFRACTION100
2.4163-2.45410.30051740.26453437X-RAY DIFFRACTION100
2.4541-2.49430.3121920.25033490X-RAY DIFFRACTION100
2.4943-2.53730.28812000.23183339X-RAY DIFFRACTION100
2.5373-2.58350.30071730.22633423X-RAY DIFFRACTION100
2.5835-2.63310.28751850.22633427X-RAY DIFFRACTION100
2.6331-2.68690.29731910.2173367X-RAY DIFFRACTION100
2.6869-2.74530.27051740.22183492X-RAY DIFFRACTION100
2.7453-2.80920.24391600.20453378X-RAY DIFFRACTION100
2.8092-2.87940.24961470.19053467X-RAY DIFFRACTION100
2.8794-2.95730.23661720.18953417X-RAY DIFFRACTION100
2.9573-3.04430.26481600.18643477X-RAY DIFFRACTION100
3.0443-3.14260.25811870.19733346X-RAY DIFFRACTION100
3.1426-3.25490.23251700.19243489X-RAY DIFFRACTION100
3.2549-3.38520.25311710.17353401X-RAY DIFFRACTION100
3.3852-3.53930.22551820.15923456X-RAY DIFFRACTION100
3.5393-3.72590.1881840.14883401X-RAY DIFFRACTION100
3.7259-3.95930.19471990.14343387X-RAY DIFFRACTION100
3.9593-4.2650.17911790.12723422X-RAY DIFFRACTION100
4.265-4.69420.14961660.12713436X-RAY DIFFRACTION100
4.6942-5.37340.16121730.13643434X-RAY DIFFRACTION100
5.3734-6.76940.20251720.1583424X-RAY DIFFRACTION100
6.7694-82.65790.18351410.15663449X-RAY DIFFRACTION99
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)
10.6622-0.10070.00811.14890.42462.7187-0.0174-0.00390.0033-0.0266-0.11680.01350.11890.02940.13330.2078-0.03510.05780.3120.02370.2919117.5978251.9935361.586
20.5301-0.0619-0.0930.97320.32933.7351-0.02590.059-0.0073-0.0747-0.15320.1538-0.0894-0.37820.13670.27540.01720.01240.3685-0.06040.3162115.9326250.7628324.2649
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 302:721)
2X-RAY DIFFRACTION2(chain B and resid 304:721)

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