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- PDB-5uo7: Structure of human neuronal nitric oxide synthase heme domain in ... -

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Basic information

Entry
Database: PDB / ID: 5uo7
TitleStructure of human neuronal nitric oxide synthase heme domain in complex with (S)-3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)propyl)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 / peptidyl-cysteine S-nitrosylase activity / 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 ...positive regulation of membrane repolarization during ventricular cardiac muscle cell action potential / negative regulation of calcium ion transport into cytosol / peptidyl-cysteine S-nitrosylase activity / 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 / positive regulation of sodium ion transmembrane transport / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of potassium ion transport / negative regulation of calcium ion transport / nitric oxide mediated signal transduction / nitric-oxide synthase (NADPH) / negative regulation of serotonin uptake / sodium channel regulator activity / regulation of cardiac muscle contraction / calcium channel regulator activity / nitric-oxide synthase activity / multicellular organismal response to stress / arginine catabolic process / xenobiotic catabolic process / striated muscle contraction / regulation of sodium ion transport / Ion homeostasis / negative regulation of blood pressure / response to hormone / photoreceptor inner segment / nitric oxide biosynthetic process / cell redox homeostasis / sarcoplasmic reticulum / cell periphery / sarcolemma / cellular response to growth factor stimulus / vasodilation / calcium-dependent protein binding / FMN binding / NADP binding / flavin adenine dinucleotide binding / response to heat / scaffold protein binding / response to lipopolysaccharide / dendritic spine / transmembrane transporter binding / response to hypoxia / cytoskeleton / calmodulin binding / 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 / 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, 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 / 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
Chem-8FD / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / 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: J. Med. Chem. / Year: 2017
Title: Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.
Authors: Cinelli, M.A. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionJan 31, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2017Provider: repository / Type: Initial release
Revision 1.1May 24, 2017Group: Database references
Revision 1.2Sep 13, 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_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)100,0719
Polymers97,5692
Non-polymers2,5027
Water7,837435
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9210 Å2
ΔGint-79 kcal/mol
Surface area34260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.307, 124.814, 165.190
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 , 5 types, 442 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 / Comment: neurotransmitter*YM
#4: Chemical ChemComp-8FD / 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-[(2S)-2-(methylamino)propyl]benzonitrile


Mass: 360.452 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24N4O
#5: Chemical ChemComp-ZN / ZINC ION


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


Mass: 18.015 Da / Num. of mol.: 435 / 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
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 4, 2016 / Details: mirrors
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.06→60 Å / Num. obs: 67875 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 5.9 % / CC1/2: 0.991 / Rmerge(I) obs: 0.16 / Rsym value: 0.16 / Net I/σ(I): 7.4
Reflection shellResolution: 2.06→2.13 Å / Redundancy: 5.6 % / Rmerge(I) obs: 5.556 / Mean I/σ(I) obs: 0.5 / Num. unique all: 4351 / CC1/2: 0.515 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSOct 15, 2015data reduction
Aimless0.5.25data scaling
REFMAC5.8.0049phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 4UH5

4uh5


Resolution: 2.06→39.207 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.07 / Phase error: 30.82
RfactorNum. reflection% reflectionSelection details
Rfree0.239 3142 4.87 %random
Rwork0.1866 ---
obs0.1892 64321 94.08 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.06→39.207 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6721 0 175 435 7331
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077164
X-RAY DIFFRACTIONf_angle_d1.1059760
X-RAY DIFFRACTIONf_dihedral_angle_d14.8262610
X-RAY DIFFRACTIONf_chiral_restr0.0411006
X-RAY DIFFRACTIONf_plane_restr0.0051231
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0584-2.08180.49411170.44582397X-RAY DIFFRACTION58
2.0818-2.10630.5617360.446968X-RAY DIFFRACTION24
2.1063-2.1320.40181650.40193069X-RAY DIFFRACTION75
2.132-2.1590.462000.37323653X-RAY DIFFRACTION89
2.159-2.18740.36731930.35183892X-RAY DIFFRACTION94
2.1874-2.21730.35331900.35373954X-RAY DIFFRACTION97
2.2173-2.2490.37442100.3364097X-RAY DIFFRACTION99
2.249-2.28260.3761750.32763954X-RAY DIFFRACTION96
2.2826-2.31830.38462170.31514068X-RAY DIFFRACTION99
2.3183-2.35630.33061900.31414070X-RAY DIFFRACTION99
2.3563-2.39690.32232400.30074050X-RAY DIFFRACTION99
2.3969-2.44050.36142410.2914006X-RAY DIFFRACTION99
2.4405-2.48740.32872120.29484105X-RAY DIFFRACTION99
2.4874-2.53820.30542430.27454038X-RAY DIFFRACTION100
2.5382-2.59330.33081950.26834134X-RAY DIFFRACTION100
2.5933-2.65360.32372290.26124046X-RAY DIFFRACTION100
2.6536-2.720.33272320.24134069X-RAY DIFFRACTION99
2.72-2.79350.29591780.21694133X-RAY DIFFRACTION100
2.7935-2.87570.25232000.19624104X-RAY DIFFRACTION100
2.8757-2.96850.23552030.1974112X-RAY DIFFRACTION100
2.9685-3.07450.25281770.20614163X-RAY DIFFRACTION100
3.0745-3.19760.26352170.20854035X-RAY DIFFRACTION100
3.1976-3.3430.26542170.17944092X-RAY DIFFRACTION100
3.343-3.51920.21122040.15964126X-RAY DIFFRACTION100
3.5192-3.73950.20692310.13984077X-RAY DIFFRACTION100
3.7395-4.0280.19222200.13044101X-RAY DIFFRACTION100
4.028-4.43280.18472150.11514075X-RAY DIFFRACTION100
4.4328-5.07310.15312120.11444078X-RAY DIFFRACTION99
5.0731-6.38710.1711940.1414112X-RAY DIFFRACTION100
6.3871-39.21420.19871840.15254115X-RAY DIFFRACTION100
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)
10.9395-0.31430.06971.34030.4482.66410.02690.01890.0326-0.1048-0.09-0.07510.10580.14380.05930.2491-0.04460.04070.34010.04090.2786117.5556254.7902361.8203
20.7987-0.18940.16551.4270.08244.07250.00090.03610.0123-0.0492-0.07090.1244-0.1122-0.24470.06060.32080.02650.04180.3985-0.04230.3053115.6947253.4967324.3485
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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