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- PDB-5uny: Structure of rat neuronal nitric oxide synthase heme domain in co... -

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Basic information

Entry
Database: PDB / ID: 5uny
TitleStructure of rat neuronal nitric oxide synthase heme domain in complex with (RS)-3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)propyl)benzonitrile
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / nitric / oxide / synthase / inhibitor / complex / heme / enzyme / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
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
Chem-8FD / ACETATE ION / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-M4R / Nitric oxide synthase 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.82 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: Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.
Authors: Cinelli, M.A. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionJan 31, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2017Provider: repository / Type: Initial release
Revision 1.1May 24, 2017Group: Database references
Revision 1.2Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_conn / struct_site
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 / _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)100,96613
Polymers97,6252
Non-polymers3,34111
Water7,314406
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9730 Å2
ΔGint-84 kcal/mol
Surface area33500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.968, 111.937, 164.978
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
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Nos1, Bnos / Organ: brain / Plasmid: pCWori / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P29476, nitric-oxide synthase (NADPH)

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Non-polymers , 7 types, 417 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-M4R / 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-[(2R)-2-(methylamino)propyl]benzonitrile


Mass: 360.452 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24N4O
#5: Chemical ChemComp-8FD / 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-[(2S)-2-(methylamino)propyl]benzonitrile


Mass: 360.452 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H24N4O
#6: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#7: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 406 / 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: brick
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.8
Details: 20-24% PEG3350, 0.1 M MES, 0.14-0.20 M ammonium acetate, 10% ethylene glycol, 30 uM SDS, 5 mM GSH

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 3, 2016 / Details: graphite
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: 1.82→50 Å / Num. obs: 86968 / % possible obs: 99.4 % / Observed criterion σ(I): -3 / Redundancy: 5.9 % / CC1/2: 0.997 / Rmerge(I) obs: 0.084 / Rsym value: 0.084 / Net I/σ(I): 12.7
Reflection shellResolution: 1.82→1.87 Å / Redundancy: 5.5 % / Rmerge(I) obs: 5.301 / Mean I/σ(I) obs: 0.4 / Num. unique all: 4105 / CC1/2: 0.373 / % possible all: 93.1

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSOct 15, 2015data reduction
Aimless0.5.15data scaling
REFMAC5.8.0049phasing
RefinementResolution: 1.82→39.226 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 1.02 / Phase error: 34.07
RfactorNum. reflection% reflectionSelection details
Rfree0.2378 3997 4.98 %random
Rwork0.1933 ---
obs0.1955 80639 91.59 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.82→39.226 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6685 0 237 406 7328
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087168
X-RAY DIFFRACTIONf_angle_d1.0989757
X-RAY DIFFRACTIONf_dihedral_angle_d15.2072601
X-RAY DIFFRACTIONf_chiral_restr0.0411002
X-RAY DIFFRACTIONf_plane_restr0.0051225
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8184-1.83910.51031280.56022285X-RAY DIFFRACTION43
1.8391-1.86070.65711410.5222522X-RAY DIFFRACTION47
1.8607-1.88340.54191650.48273186X-RAY DIFFRACTION61
1.8834-1.90720.52571140.47382583X-RAY DIFFRACTION72
1.9072-1.93230.52012100.50523928X-RAY DIFFRACTION81
1.9323-1.95880.45332870.39865135X-RAY DIFFRACTION98
1.9588-1.98680.40243050.36385173X-RAY DIFFRACTION98
1.9868-2.01640.37792720.36115217X-RAY DIFFRACTION99
2.0164-2.04790.34992360.33325242X-RAY DIFFRACTION99
2.0479-2.08150.38892860.36255220X-RAY DIFFRACTION97
2.0815-2.11740.40482690.32415177X-RAY DIFFRACTION99
2.1174-2.15590.36672190.29065339X-RAY DIFFRACTION99
2.1559-2.19740.34642440.28525219X-RAY DIFFRACTION99
2.1974-2.24220.32752820.26915305X-RAY DIFFRACTION99
2.2422-2.2910.41653110.30075062X-RAY DIFFRACTION97
2.291-2.34430.30662970.23175145X-RAY DIFFRACTION97
2.3443-2.40290.28042510.21745229X-RAY DIFFRACTION99
2.4029-2.46780.28192700.22885341X-RAY DIFFRACTION100
2.4678-2.54040.29892580.21215233X-RAY DIFFRACTION100
2.5404-2.62240.25253040.20755289X-RAY DIFFRACTION100
2.6224-2.71610.27392450.20325304X-RAY DIFFRACTION100
2.7161-2.82480.23672680.18295269X-RAY DIFFRACTION100
2.8248-2.95340.21012750.1875285X-RAY DIFFRACTION100
2.9534-3.1090.24013020.18595172X-RAY DIFFRACTION98
3.109-3.30370.19982540.17445303X-RAY DIFFRACTION100
3.3037-3.55860.18552700.15165302X-RAY DIFFRACTION100
3.5586-3.91650.20053120.13955229X-RAY DIFFRACTION100
3.9165-4.48250.15552650.1235228X-RAY DIFFRACTION99
4.4825-5.64480.18693130.12845271X-RAY DIFFRACTION100
5.6448-39.23530.17732710.16035251X-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)
10.935-0.1602-0.37591.61850.14728.0834-0.05880.147-0.02260.0064-0.12440.1197-0.1751-0.51650.09090.28230.0076-0.00170.2682-0.00160.260111.32314.873922.732
21.0605-0.2514-0.11711.40340.4374.36770.0059-0.03220.0735-0.1275-0.0864-0.02590.06550.12290.0620.2184-0.0140.05150.23120.02830.242112.45954.870260.2343
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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