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

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Basic information

Entry
Database: PDB / ID: 6auv
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with 4-Methyl-6-(2-(5-(3-((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


Nitric oxide stimulates guanylate cyclase / negative regulation of hepatic stellate cell contraction / positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / retrograde trans-synaptic signaling by nitric oxide / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / azurophil granule / negative regulation of vasoconstriction / positive regulation of sodium ion transmembrane transport ...Nitric oxide stimulates guanylate cyclase / negative regulation of hepatic stellate cell contraction / positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / retrograde trans-synaptic signaling by nitric oxide / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / azurophil granule / negative regulation of vasoconstriction / positive regulation of sodium ion transmembrane transport / postsynaptic specialization, intracellular component / nitric oxide metabolic process / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / response to nitric oxide / Ion homeostasis / negative regulation of cytosolic calcium ion concentration / peptidyl-cysteine S-nitrosylation / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of potassium ion transport / negative regulation of calcium ion transport / behavioral response to cocaine / regulation of postsynaptic membrane potential / calyx of Held / regulation of neurogenesis / postsynaptic density, intracellular component / negative regulation of serotonin uptake / nitric-oxide synthase (NADPH) / multicellular organismal response to stress / response to vitamin E / sodium channel regulator activity / nitric oxide mediated signal transduction / negative regulation of insulin secretion / nitric-oxide synthase activity / xenobiotic catabolic process / arginine catabolic process / NADPH binding / striated muscle contraction / regulation of sodium ion transport / nitric oxide-cGMP-mediated signaling / T-tubule / nitric oxide biosynthetic process / cellular response to epinephrine stimulus / sarcoplasmic reticulum membrane / negative regulation of blood pressure / photoreceptor inner segment / response to hormone / response to nutrient levels / secretory granule / sarcoplasmic reticulum / positive regulation of long-term synaptic potentiation / establishment of localization in cell / response to activity / cell periphery / female pregnancy / response to nicotine / phosphoprotein binding / response to lead ion / establishment of protein localization / potassium ion transport / caveola / cellular response to growth factor stimulus / response to organic cyclic compound / sarcolemma / Z disc / response to peptide hormone / cellular response to mechanical stimulus / response to estrogen / vasodilation / calcium-dependent protein binding / calcium ion transport / FMN binding / positive regulation of peptidyl-serine phosphorylation / flavin adenine dinucleotide binding / NADP binding / ATPase binding / response to heat / scaffold protein binding / nuclear membrane / response to ethanol / negative regulation of neuron apoptotic process / mitochondrial outer membrane / transmembrane transporter binding / response to lipopolysaccharide / dendritic spine / postsynaptic density / cytoskeleton / calmodulin binding / response to hypoxia / membrane raft / negative regulation of cell population proliferation / glutamatergic synapse / dendrite / heme binding / synapse / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / 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 / 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 / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-W79 / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.76 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
Water9,926551
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9850 Å2
ΔGint-85 kcal/mol
Surface area33410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.120, 111.181, 164.173
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, 560 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-W79 / 4-methyl-6-[2-(5-{3-[(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.: 551 / 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: Feb 26, 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: 1.76→55 Å / Num. obs: 95459 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 5.8 % / CC1/2: 0.962 / Rmerge(I) obs: 0.102 / Rpim(I) all: 0.047 / Rsym value: 0.102 / Net I/σ(I): 10.2
Reflection shellResolution: 1.76→1.8 Å / Redundancy: 4.7 % / Rmerge(I) obs: 2.807 / Mean I/σ(I) obs: 0.5 / Num. unique obs: 4449 / CC1/2: 0.471 / Rpim(I) all: 1.396 / Rsym value: 2.807 / % possible all: 95.4

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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: 1.76→38.999 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 0.94 / Phase error: 30.52
RfactorNum. reflection% reflectionSelection details
Rfree0.2223 4642 4.99 %random
Rwork0.184 ---
obs0.1859 92803 96.67 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.76→38.999 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6704 0 179 551 7434
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077141
X-RAY DIFFRACTIONf_angle_d1.119722
X-RAY DIFFRACTIONf_dihedral_angle_d14.4582596
X-RAY DIFFRACTIONf_chiral_restr0.041004
X-RAY DIFFRACTIONf_plane_restr0.0051231
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7586-1.77860.48581660.47862916X-RAY DIFFRACTION50
1.7786-1.79950.42982880.42724950X-RAY DIFFRACTION85
1.7995-1.82150.41243120.40325456X-RAY DIFFRACTION95
1.8215-1.84450.43193030.38815697X-RAY DIFFRACTION98
1.8445-1.86880.39973290.36895681X-RAY DIFFRACTION97
1.8688-1.89440.44582390.36025611X-RAY DIFFRACTION98
1.8944-1.92140.4642940.38225663X-RAY DIFFRACTION96
1.9214-1.95010.33692920.3285629X-RAY DIFFRACTION97
1.9501-1.98060.36743340.30115706X-RAY DIFFRACTION99
1.9806-2.01310.34442750.28935771X-RAY DIFFRACTION99
2.0131-2.04780.31722770.28255692X-RAY DIFFRACTION99
2.0478-2.0850.30313180.27775595X-RAY DIFFRACTION95
2.085-2.12510.30812550.24045715X-RAY DIFFRACTION100
2.1251-2.16850.28192650.2345884X-RAY DIFFRACTION100
2.1685-2.21560.32692800.22055741X-RAY DIFFRACTION100
2.2156-2.26720.29913210.23825716X-RAY DIFFRACTION98
2.2672-2.32390.25543520.19955680X-RAY DIFFRACTION100
2.3239-2.38670.23942890.18945834X-RAY DIFFRACTION100
2.3867-2.45690.27952920.20485792X-RAY DIFFRACTION100
2.4569-2.53620.26112970.18995740X-RAY DIFFRACTION99
2.5362-2.62680.25183120.17835797X-RAY DIFFRACTION100
2.6268-2.7320.20342790.18235801X-RAY DIFFRACTION99
2.732-2.85630.20932860.17215776X-RAY DIFFRACTION100
2.8563-3.00680.22263150.16735768X-RAY DIFFRACTION100
3.0068-3.19510.2333400.17665762X-RAY DIFFRACTION100
3.1951-3.44170.18142690.15385810X-RAY DIFFRACTION100
3.4417-3.78770.18133210.13685753X-RAY DIFFRACTION100
3.7877-4.33520.14062990.11895799X-RAY DIFFRACTION100
4.3352-5.45950.14653460.11775715X-RAY DIFFRACTION100
5.4595-39.00810.14982990.14215799X-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)
10.8999-0.0904-0.3991.1888-0.0575.8206-0.06860.1574-0.0204-0.0373-0.01980.07240.1291-0.39330.03950.2067-0.02670.01130.2193-0.00860.19611.335.066122.3703
20.7959-0.1636-0.09191.06440.33332.6975-0.01610.0080.0203-0.1309-0.0391-0.02370.19570.0880.04680.17560.00390.02910.16810.01760.193312.09014.787759.6812
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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