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- PDB-4kcj: Structure of neuronal nitric oxide synthase heme domain in comple... -

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Basic information

Entry
Database: PDB / ID: 4kcj
TitleStructure of neuronal nitric oxide synthase heme domain in complex with N,N'-((ethane-1,2-diylbis(oxy))bis(3,1-phenylene))bis(thiophene-2-carboximidamide)
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / nitric oxide synthase / 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 / Chem-H36 / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.05 Å
AuthorsLi, H. / Poulos, T.L.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Potent and Selective Double-Headed Thiophene-2-carboximidamide Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma.
Authors: Huang, H. / Li, H. / Yang, S. / Chreifi, G. / Martasek, P. / Roman, L.J. / Meyskens, F.L. / Poulos, T.L. / Silverman, R.B.
History
DepositionApr 24, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 12, 2014Provider: repository / Type: Initial release
Revision 1.1Feb 26, 2014Group: Database references
Revision 1.2Nov 15, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Sep 20, 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 / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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 / _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)100,44911
Polymers97,6252
Non-polymers2,8249
Water4,666259
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10060 Å2
ΔGint-126 kcal/mol
Surface area32720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.802, 111.032, 164.730
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 / N-NOS / nNOS / Peptidyl-cysteine S- ...BNOS / Constitutive NOS / NC-NOS / NOS type I / Neuronal NOS / N-NOS / nNOS / Peptidyl-cysteine S-nitrosylase NOS1


Mass: 48812.527 Da / Num. of mol.: 2 / Fragment: heme domain (UNP residues 297-718)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Nos1, Bnos / 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, 268 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-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#5: Chemical ChemComp-H36 / N,N'-[ethane-1,2-diylbis(oxybenzene-3,1-diyl)]dithiophene-2-carboximidamide


Mass: 462.587 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H22N4O2S2
#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.: 259 / 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: 2.43 Å3/Da / Density % sol: 49.31 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.8
Details: 20-22% PEG3350, 0.1 M MES, 0.14-0.20 M ammonium acetate, 10% ethylene glycol, 5 mM GSH, 30 uM SDS, pH 5.8, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.979 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jul 8, 2012 / Details: Rh coated flat mirror, toroidal focusing mirror
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: 2.05→92.19 Å / Num. obs: 61070 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 3.6 % / Biso Wilson estimate: 35 Å2 / Rmerge(I) obs: 0.055 / Rsym value: 0.055 / Net I/σ(I): 25.1
Reflection shellResolution: 2.05→2.09 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.799 / Mean I/σ(I) obs: 2.1 / Rsym value: 0.799 / % possible all: 97.8

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Processing

Software
NameVersionClassification
Blu-IceIcedata collection
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1OM4

1om4


Resolution: 2.05→92.19 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.94 / SU B: 12.103 / SU ML: 0.158 / Cross valid method: THROUGHOUT / ESU R: 0.202 / ESU R Free: 0.178 / Stereochemistry target values: Engh & Huber
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.24234 2992 5 %RANDOM
Rwork0.19465 ---
obs0.19703 57366 99.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 53.378 Å2
Baniso -1Baniso -2Baniso -3
1-2.89 Å20 Å20 Å2
2--0.03 Å20 Å2
3----2.92 Å2
Refinement stepCycle: LAST / Resolution: 2.05→92.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6658 0 193 259 7110
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.027064
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.1091.9749611
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3315816
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.20123.855332
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.666151168
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2391541
X-RAY DIFFRACTIONr_chiral_restr0.1010.2993
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0215449
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.05→2.103 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.43 201 -
Rwork0.383 3830 -
obs--98.15 %
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)
10.5698-0.1246-0.19351.0721-0.62097.0677-0.04010.06660.0150.0066-0.06360.08070.1199-0.37570.10360.15930.00290.01830.1328-0.01720.014311.3684.51122.594
20.7952-0.2075-0.16041.02110.56332.6615-0.01350.00320.0967-0.1247-0.0405-0.04590.10390.06330.05390.13680.01590.02750.10950.02240.021912.3234.63959.902
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A299 - 716
2X-RAY DIFFRACTION1A801 - 804
3X-RAY DIFFRACTION2B299 - 718
4X-RAY DIFFRACTION2B801 - 804

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