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

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Basic information

Entry
Database: PDB / ID: 6auu
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with 6-(3-(3-(dimethylamino)propyl)-5-(trifluoromethyl)phenethyl)-4-methylpyridin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor complex heme enzyme
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 / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / response to vitamin B3 / azurophil granule / postsynaptic specialization, intracellular component / negative regulation of vasoconstriction ...negative regulation of hepatic stellate cell contraction / Nitric oxide stimulates guanylate cyclase / positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / response to vitamin B3 / azurophil granule / postsynaptic specialization, intracellular component / negative regulation of vasoconstriction / negative regulation of cytosolic calcium ion concentration / Ion homeostasis / response to 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 / regulation of postsynaptic membrane potential / cadmium ion binding / positive regulation of the force of heart contraction / behavioral response to cocaine / negative regulation of potassium ion transport / negative regulation of calcium ion transport / regulation of neurogenesis / nitric oxide mediated signal transduction / nitric-oxide synthase (NADPH) / sodium channel regulator activity / negative regulation of serotonin uptake / response to vitamin E / postsynaptic density, intracellular component / nitric-oxide synthase activity / multicellular organismal response to stress / xenobiotic catabolic process / L-arginine catabolic process / negative regulation of insulin secretion / NADPH binding / striated muscle contraction / regulation of sodium ion transport / nitric oxide-cGMP-mediated signaling / nitric oxide metabolic process / negative regulation of blood pressure / response to hormone / sarcoplasmic reticulum membrane / cellular response to epinephrine stimulus / photoreceptor inner segment / T-tubule / nitric oxide biosynthetic process / calyx of Held / secretory granule / sarcoplasmic reticulum / positive regulation of long-term synaptic potentiation / response to activity / cell periphery / female pregnancy / establishment of localization in cell / phosphoprotein binding / response to nicotine / establishment of protein localization / response to lead ion / response to nutrient levels / potassium ion transport / : / sarcolemma / cellular response to growth factor stimulus / caveola / response to peptide hormone / Z disc / response to estrogen / cellular response to mechanical stimulus / calcium ion transport / calcium-dependent protein binding / vasodilation / FMN binding / flavin adenine dinucleotide binding / NADP binding / ATPase binding / response to heat / scaffold protein binding / nuclear membrane / dendritic spine / negative regulation of neuron apoptotic process / response to lipopolysaccharide / response to ethanol / mitochondrial outer membrane / transmembrane transporter binding / cytoskeleton / response to hypoxia / calmodulin binding / postsynaptic density / membrane raft / negative regulation of cell population proliferation / synapse / heme binding / 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 / protein-containing complex
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
ACETATE ION / Chem-BY7 / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / D-MANNITOL / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.85 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)100,50814
Polymers97,6252
Non-polymers2,88312
Water7,332407
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10500 Å2
ΔGint-111 kcal/mol
Surface area32720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.710, 111.060, 164.500
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 / Fragment: UNP residues 297-718
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 , 8 types, 419 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-BY7 / 6-(2-{3-[3-(dimethylamino)propyl]-5-(trifluoromethyl)phenyl}ethyl)-4-methylpyridin-2-amine


Mass: 365.436 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H26F3N3
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#6: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#8: Chemical ChemComp-MTL / D-MANNITOL


Mass: 182.172 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O6 / Comment: medication*YM
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 407 / 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: BL14-1 / Wavelength: 1.1808 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Dec 16, 2015 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1808 Å / Relative weight: 1
ReflectionResolution: 1.85→55 Å / Num. obs: 81744 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 4 % / CC1/2: 0.997 / Rmerge(I) obs: 0.102 / Rpim(I) all: 0.087 / Rsym value: 0.102 / Net I/σ(I): 5.3
Reflection shellResolution: 1.85→1.9 Å / Redundancy: 4 % / Rmerge(I) obs: 2.199 / Mean I/σ(I) obs: 0.3 / Num. unique obs: 4365 / CC1/2: 0.349 / Rpim(I) all: 1.848 / Rsym value: 2.199 / % possible all: 99.8

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Processing

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

1om4


Resolution: 1.85→52.613 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 0.02 / Phase error: 32.36
RfactorNum. reflection% reflectionSelection details
Rfree0.2401 4028 4.97 %random
Rwork0.1992 ---
obs0.2013 81572 99.78 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.85→52.613 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6685 0 195 407 7287
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087110
X-RAY DIFFRACTIONf_angle_d1.1689676
X-RAY DIFFRACTIONf_dihedral_angle_d15.252589
X-RAY DIFFRACTIONf_chiral_restr0.0411005
X-RAY DIFFRACTIONf_plane_restr0.0061219
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.8710.47922560.44664789X-RAY DIFFRACTION100
1.871-1.8930.48622420.41164983X-RAY DIFFRACTION100
1.893-1.91610.40482490.39565044X-RAY DIFFRACTION99
1.9161-1.94040.41752700.39584815X-RAY DIFFRACTION100
1.9404-1.96590.40412680.37224901X-RAY DIFFRACTION100
1.9659-1.99290.39932810.36244964X-RAY DIFFRACTION99
1.9929-2.02130.38342240.34534879X-RAY DIFFRACTION99
2.0213-2.05150.31962750.32694960X-RAY DIFFRACTION100
2.0515-2.08360.37282620.32294907X-RAY DIFFRACTION100
2.0836-2.11770.3352150.30754974X-RAY DIFFRACTION100
2.1177-2.15420.33572390.2935036X-RAY DIFFRACTION100
2.1542-2.19340.3372160.29314887X-RAY DIFFRACTION100
2.1934-2.23560.41532720.27864973X-RAY DIFFRACTION100
2.2356-2.28120.31733040.26594862X-RAY DIFFRACTION100
2.2812-2.33080.30182850.24674950X-RAY DIFFRACTION100
2.3308-2.38510.2982370.23474917X-RAY DIFFRACTION100
2.3851-2.44470.3242510.23524976X-RAY DIFFRACTION100
2.4447-2.51080.29152340.22484929X-RAY DIFFRACTION100
2.5108-2.58470.27422850.21324967X-RAY DIFFRACTION100
2.5847-2.66810.27352380.2094900X-RAY DIFFRACTION100
2.6681-2.76350.24652400.20754995X-RAY DIFFRACTION100
2.7635-2.87410.28312600.20164957X-RAY DIFFRACTION100
2.8741-3.00490.22632690.18654923X-RAY DIFFRACTION100
3.0049-3.16330.21822870.18234907X-RAY DIFFRACTION100
3.1633-3.36140.21932410.16994967X-RAY DIFFRACTION100
3.3614-3.62090.17782670.14954938X-RAY DIFFRACTION100
3.6209-3.98520.21112540.13894987X-RAY DIFFRACTION100
3.9852-4.56160.16792760.12674907X-RAY DIFFRACTION100
4.5616-5.7460.16383000.13264932X-RAY DIFFRACTION100
5.746-52.63440.16222400.15864931X-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)
10.8663-0.0556-0.47061.5416-0.35386.8882-0.05990.1202-0.01450.0866-0.07370.09110.1197-0.44210.0730.2432-0.00340.0070.2363-0.01810.249511.31854.924922.5042
20.9398-0.1772-0.15120.99680.41683.12840.01340.00770.0325-0.1629-0.0666-0.0350.08870.10440.04020.22480.01420.03420.19470.02230.223612.23714.744659.8837
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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