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- PDB-4d2z: Structure of rat neuronal nitric oxide synthase heme domain in co... -

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Basic information

Entry
Database: PDB / ID: 4d2z
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with (1S,2S)-2-(3-fluorobenzyl)-N-{2-[2-(1H-imidazol-1-YL)pyrimidin-4-YL]ethyl}cyclopropanamine
ComponentsNITRIC OXIDE SYNTHASE, BRAIN
KeywordsOXIDOREDUCTASE / NITRIC OXIDE SYNTHASE / INHIBITOR COMPLEX
Function / homology
Function and homology information


positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / Nitric oxide stimulates guanylate cyclase / negative regulation of hepatic stellate cell contraction / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / azurophil granule / negative regulation of vasoconstriction / retrograde trans-synaptic signaling by nitric oxide / Ion homeostasis ...positive regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / Nitric oxide stimulates guanylate cyclase / negative regulation of hepatic stellate cell contraction / synaptic signaling by nitric oxide / negative regulation of iron ion transmembrane transport / ROS and RNS production in phagocytes / azurophil granule / negative regulation of vasoconstriction / retrograde trans-synaptic signaling by nitric oxide / Ion homeostasis / positive regulation of sodium ion transmembrane transport / response to nitric oxide / postsynaptic specialization, intracellular component / negative regulation of cytosolic calcium ion concentration / peptidyl-cysteine S-nitrosylation / behavioral response to cocaine / postsynaptic density, intracellular component / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of potassium ion transport / calyx of Held / negative regulation of calcium ion transport / negative regulation of serotonin uptake / sodium channel regulator activity / regulation of neurogenesis / striated muscle contraction / negative regulation of insulin secretion / regulation of postsynaptic membrane potential / response to vitamin E / nitric-oxide synthase (NADPH) / multicellular organismal response to stress / xenobiotic catabolic process / nitric-oxide synthase activity / negative regulation of peptidyl-serine phosphorylation / nitric oxide mediated signal transduction / arginine catabolic process / NADPH binding / regulation of sodium ion transport / response to organonitrogen compound / sarcoplasmic reticulum membrane / T-tubule / cellular response to epinephrine stimulus / photoreceptor inner segment / negative regulation of blood pressure / nitric oxide biosynthetic process / response to hormone / response to nutrient levels / response to activity / response to nicotine / muscle contraction / sarcoplasmic reticulum / secretory granule / female pregnancy / positive regulation of long-term synaptic potentiation / cell periphery / establishment of localization in cell / phosphoprotein binding / response to lead ion / sarcolemma / establishment of protein localization / potassium ion transport / response to organic cyclic compound / response to peptide hormone / cellular response to growth factor stimulus / Z disc / vasodilation / cellular response to mechanical stimulus / response to estrogen / calcium-dependent protein binding / calcium ion transport / FMN binding / flavin adenine dinucleotide binding / positive regulation of peptidyl-serine phosphorylation / NADP binding / ATPase binding / response to heat / scaffold protein binding / response to ethanol / nuclear membrane / negative regulation of neuron apoptotic process / mitochondrial outer membrane / transmembrane transporter binding / response to lipopolysaccharide / dendritic spine / postsynaptic density / response to hypoxia / cytoskeleton / calmodulin binding / membrane raft / negative regulation of cell population proliferation / dendrite / glutamatergic synapse / synapse / heme binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / positive regulation of DNA-templated transcription / 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, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 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, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain 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-K9L / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRATTUS NORVEGICUS (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.886 Å
AuthorsLi, H. / Poulos, T.L.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Novel 2,4-Disubstituted Pyrimidines as Potent, Selective, and Cell-Permeable Inhibitors of Neuronal Nitric Oxide Synthase.
Authors: Mukherjee, P. / Li, H. / Sevrioukova, I. / Chreifi, G. / Martasek, P. / Roman, L.J. / Poulos, T.L. / Silverman, R.B.
History
DepositionOct 20, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 24, 2014Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2015Group: Database references

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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)100,19911
Polymers97,6252
Non-polymers2,5749
Water7,116395
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9680 Å2
ΔGint-91.5 kcal/mol
Surface area33240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.820, 111.320, 164.200
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 / NEURONAL NITRIC OXIDE SYNTHASE


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) / 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, 404 molecules

#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN / Tetrahydrobiopterin


Mass: 241.247 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#4: Chemical ChemComp-K9L / (1S,2S)-2-(3-fluorobenzyl)-N-{2-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]ethyl}cyclopropanamine


Mass: 337.394 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H20FN5
#5: Chemical ChemComp-ACT / ACETATE ION / Acetate


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 / Water


Mass: 18.015 Da / Num. of mol.: 395 / 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: 2.46 Å3/Da / Density % sol: 50.1 %
Description: RMERGE GREATER THAN 1.0 RPIM GREATER THEN 1.0 CC ONE HALF 0.435
Crystal growpH: 5.8
Details: 20-24% PEG3350, 0.1M MES, 10% ETHYLENE GLYCOL, 140-200 MM AMMONIUM ACETATE, 5 MM GSH, 35UM SDS, pH 5.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 6, 2014 / Details: MIRRORS
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.89→50 Å / Num. obs: 77018 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 7.3 % / Biso Wilson estimate: 25.45 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 22.1
Reflection shellResolution: 1.89→1.91 Å / Redundancy: 4.8 % / Rmerge(I) obs: 1 / Mean I/σ(I) obs: 0.4 / % possible all: 97.6

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
HKL-2000data reduction
SCALEPACKdata scaling
REFMACphasing
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.886→49.417 Å / SU ML: 0.23 / σ(F): 1.35 / Phase error: 26.76 / Stereochemistry target values: ML
Details: RESIDUES 339 TO 349 IN CHAIN A AND 339 TO 347 IN CHAIN B ARE DISORDERED.
RfactorNum. reflection% reflection
Rfree0.2274 2878 4.9 %
Rwork0.1778 --
obs0.1803 58392 75.35 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.886→49.417 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6659 0 179 395 7233
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087061
X-RAY DIFFRACTIONf_angle_d1.1729613
X-RAY DIFFRACTIONf_dihedral_angle_d15.7442566
X-RAY DIFFRACTIONf_chiral_restr0.076995
X-RAY DIFFRACTIONf_plane_restr0.0051213
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8858-1.91680.2809160.2428421X-RAY DIFFRACTION12
1.9168-1.94980.2366320.2475566X-RAY DIFFRACTION17
1.9498-1.98530.3103420.2443746X-RAY DIFFRACTION22
1.9853-2.02340.3259500.2324979X-RAY DIFFRACTION28
2.0234-2.06470.2625640.26041214X-RAY DIFFRACTION35
2.0647-2.10960.3363730.26191571X-RAY DIFFRACTION45
2.1096-2.15870.2918950.24242100X-RAY DIFFRACTION60
2.1587-2.21270.31821160.2422599X-RAY DIFFRACTION76
2.2127-2.27250.38181660.28822986X-RAY DIFFRACTION85
2.2725-2.33940.28552010.22153391X-RAY DIFFRACTION99
2.3394-2.41490.26921780.21133489X-RAY DIFFRACTION100
2.4149-2.50120.32961650.20663493X-RAY DIFFRACTION100
2.5012-2.60140.2461900.19333504X-RAY DIFFRACTION100
2.6014-2.71970.22921690.20763507X-RAY DIFFRACTION100
2.7197-2.86310.24691720.19053518X-RAY DIFFRACTION100
2.8631-3.04250.25431960.18563509X-RAY DIFFRACTION100
3.0425-3.27730.24141840.17563508X-RAY DIFFRACTION100
3.2773-3.60710.19051920.15743534X-RAY DIFFRACTION100
3.6071-4.12880.20391830.13923554X-RAY DIFFRACTION100
4.1288-5.20090.16462070.12633576X-RAY DIFFRACTION100
5.2009-49.43440.17691870.15743749X-RAY DIFFRACTION99
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)
11.0207-0.2119-0.561.4361-0.22137.1368-0.10150.1325-0.01820.0574-0.06740.09690.2184-0.47470.06380.1102-0.03410.02130.1502-0.02150.193511.30444.826622.4351
20.953-0.0976-0.10881.30070.54283.5433-0.0178-0.01740.0698-0.1332-0.0606-0.03780.16840.09060.03150.10080.04730.03690.13560.01570.184312.28064.916359.896
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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