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

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Basic information

Entry
Database: PDB / ID: 6pot
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 7-(3-(Aminomethyl)-4-(thiazol-5-ylmethoxy)phenyl)-4-methylquinolin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/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 / regulation of neurogenesis / negative regulation of serotonin uptake / 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 / response to hormone / Ion homeostasis / 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 / NADP binding / flavin adenine dinucleotide 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-OU7 / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.3 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: 2020
Title: First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.
Authors: Cinelli, M.A. / Reidl, C.T. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionJul 5, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1May 27, 2020Group: 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 1.2Oct 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

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)100,37912
Polymers97,5692
Non-polymers2,81010
Water6,630368
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10100 Å2
ΔGint-84 kcal/mol
Surface area34190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.370, 122.760, 164.179
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 / 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, 378 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-OU7 / 7-{3-(aminomethyl)-4-[(1,3-thiazol-5-yl)methoxy]phenyl}-4-methylquinolin-2-amine


Mass: 376.475 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H20N4OS / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / 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.: 368 / 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: 2.75 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: SSRL / Beamline: BL14-1 / Wavelength: 1.195 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jul 12, 2018 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.195 Å / Relative weight: 1
ReflectionResolution: 2.3→70 Å / Num. obs: 44912 / % possible obs: 94.8 % / Observed criterion σ(I): -3 / Redundancy: 5.3 % / CC1/2: 0.996 / Rmerge(I) obs: 0.09 / Rpim(I) all: 0.063 / Rsym value: 0.09 / Net I/σ(I): 8.9
Reflection shellResolution: 2.3→2.42 Å / Redundancy: 5.2 % / Rmerge(I) obs: 1.264 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 4330 / CC1/2: 0.573 / Rpim(I) all: 0.892 / Rsym value: 1.264 / % possible all: 93.8

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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: 4UH5

4uh5


Resolution: 2.3→68.239 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 0.35 / Phase error: 27.89
RfactorNum. reflection% reflectionSelection details
Rfree0.239 3995 4.85 %random
Rwork0.1773 ---
obs0.1803 44890 90.76 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.3→68.239 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6750 0 193 368 7311
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077191
X-RAY DIFFRACTIONf_angle_d1.0369792
X-RAY DIFFRACTIONf_dihedral_angle_d17.9034193
X-RAY DIFFRACTIONf_chiral_restr0.051008
X-RAY DIFFRACTIONf_plane_restr0.0051236
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.32710.34881160.29942687X-RAY DIFFRACTION89
2.3271-2.35550.3771650.32142652X-RAY DIFFRACTION90
2.3555-2.38530.39161530.31122666X-RAY DIFFRACTION90
2.3853-2.41670.40671450.30292667X-RAY DIFFRACTION90
2.4167-2.44980.3251280.29372679X-RAY DIFFRACTION90
2.4498-2.48480.31471580.27692728X-RAY DIFFRACTION91
2.4848-2.52190.35241580.26232690X-RAY DIFFRACTION91
2.5219-2.56130.26061350.24142727X-RAY DIFFRACTION91
2.5613-2.60330.3071410.23642701X-RAY DIFFRACTION91
2.6033-2.64820.32971430.23222718X-RAY DIFFRACTION92
2.6482-2.69630.2781770.23052682X-RAY DIFFRACTION92
2.6963-2.74820.31651150.22662794X-RAY DIFFRACTION91
2.7482-2.80430.28161330.22452684X-RAY DIFFRACTION91
2.8043-2.86520.29061240.21422701X-RAY DIFFRACTION90
2.8652-2.93190.32251380.22492761X-RAY DIFFRACTION91
2.9319-3.00520.28811170.21032604X-RAY DIFFRACTION88
3.0052-3.08650.24051090.19952461X-RAY DIFFRACTION81
3.0865-3.17730.22631210.19552696X-RAY DIFFRACTION91
3.1773-3.27980.26731310.1812850X-RAY DIFFRACTION95
3.2798-3.39710.24061580.17632762X-RAY DIFFRACTION94
3.3971-3.53310.25341480.16582803X-RAY DIFFRACTION94
3.5331-3.69390.21181500.1592789X-RAY DIFFRACTION94
3.6939-3.88860.19161440.14662753X-RAY DIFFRACTION93
3.8886-4.13220.211480.13962776X-RAY DIFFRACTION93
4.1322-4.45120.20231450.13012740X-RAY DIFFRACTION92
4.4512-4.8990.17731420.12712730X-RAY DIFFRACTION91
4.899-5.60760.21091250.14412672X-RAY DIFFRACTION89
5.6076-7.06390.19481190.16042531X-RAY DIFFRACTION85
7.0639-68.26850.2051090.15712747X-RAY DIFFRACTION91
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)
10.6543-0.4448-0.11721.26220.23972.417-0.00690.00790.0248-0.0444-0.1028-0.0470.13790.14920.08510.2069-0.02510.05120.27920.04080.299117.7112250.7857359.0249
20.6175-0.2104-0.35881.03260.35824.55810.03960.0888-0.025-0.0638-0.12270.1355-0.0201-0.44640.06230.2230.00250.02060.2951-0.04170.2923116.0931249.3851321.7908
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

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