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- PDB-5uo2: Structure of human neuronal nitric oxide synthase heme domain in ... -

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Basic information

Entry
Database: PDB / ID: 5uo2
TitleStructure of human neuronal nitric oxide synthase heme domain in complex with 7-[(3-Ethyl-5-((methylamino)methyl)phenoxy)methyl]quinolin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE inhibitor / nitric oxide synthase / inhibitor complex / heme enzyme / OXIDOREDUCTASE-OXIDOREDUCTASE inhibitor complex
Function / homology
Function and homology information


positive regulation of membrane repolarization during ventricular cardiac muscle cell action potential / negative regulation of calcium ion transport into cytosol / Nitric oxide stimulates guanylate cyclase / myoblast fusion / ROS and RNS production in phagocytes / tetrahydrobiopterin binding / arginine binding / regulation of cardiac muscle contraction by calcium ion signaling / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / synaptic signaling by nitric oxide ...positive regulation of membrane repolarization during ventricular cardiac muscle cell action potential / negative regulation of calcium ion transport into cytosol / Nitric oxide stimulates guanylate cyclase / myoblast fusion / ROS and RNS production in phagocytes / tetrahydrobiopterin binding / arginine binding / regulation of cardiac muscle contraction by calcium ion signaling / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / synaptic signaling by 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 / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of calcium ion transport / negative regulation of potassium ion transport / regulation of postsynaptic membrane potential / nitric oxide mediated signal transduction / nitric-oxide synthase (NADPH) / sodium channel regulator activity / negative regulation of serotonin uptake / regulation of neurogenesis / regulation of cardiac muscle contraction / nitric-oxide synthase activity / multicellular organismal response to stress / xenobiotic catabolic process / L-arginine catabolic process / striated muscle contraction / regulation of sodium ion transport / negative regulation of blood pressure / Ion homeostasis / response to hormone / nitric oxide biosynthetic process / photoreceptor inner segment / T-tubule / sarcoplasmic reticulum membrane / cell redox homeostasis / calyx of Held / sarcoplasmic reticulum / cell periphery / calcium channel regulator activity / establishment of localization in cell / sarcolemma / caveola / cellular response to growth factor stimulus / potassium ion transport / vasodilation / Z disc / calcium-dependent protein binding / calcium ion transport / FMN binding / flavin adenine dinucleotide binding / NADP binding / positive regulation of neuron apoptotic process / response to heat / scaffold protein binding / response to lipopolysaccharide / dendritic spine / transmembrane transporter binding / cytoskeleton / calmodulin binding / response to hypoxia / postsynaptic density / membrane raft / heme binding / synapse / positive regulation of DNA-templated transcription / perinuclear region of cytoplasm / positive regulation of transcription by RNA polymerase II / protein-containing complex / mitochondrion / nucleoplasm / nucleus / plasma membrane / cytoplasm / cytosol
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 / PDZ 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 / 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-8J4 / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.947 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 27, 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
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)100,26912
Polymers97,5692
Non-polymers2,70010
Water11,115617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10020 Å2
ΔGint-85 kcal/mol
Surface area33770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.344, 122.799, 165.266
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 / Constitutive NOS / NC-NOS / NOS type I / Neuronal NOS / nNOS / Peptidyl-cysteine S-nitrosylase NOS1 / bNOS


Mass: 48784.496 Da / Num. of mol.: 2 / Fragment: UNP residues 302-722 / Mutation: R354A,G357D
Source method: isolated from a genetically manipulated source
Details: Residues 345 to 349 are disordered. / Source: (gene. exp.) Homo sapiens (human) / Gene: NOS1 / Organ: brain / Plasmid: pCWori / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P29475, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 627 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
#4: Chemical ChemComp-8J4 / 7-({3-ethyl-5-[(methylamino)methyl]phenoxy}methyl)quinolin-2-amine


Mass: 321.416 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C20H23N3O
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#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.: 617 / 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: 2.74 Å3/Da / Density % sol: 55.2 % / Description: plate
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: 8% PEG3350,35mM citric acid,65mM Bis-Tris-Propane,10% glycerol,5mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97945 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 3, 2016 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97945 Å / Relative weight: 1
ReflectionResolution: 1.94→60 Å / Num. obs: 76250 / % possible obs: 99.4 % / Observed criterion σ(I): -3 / Redundancy: 6 % / CC1/2: 0.895 / Rmerge(I) obs: 0.122 / Rsym value: 0.122 / Net I/σ(I): 9.1
Reflection shellResolution: 1.94→2 Å / Redundancy: 5.7 % / Rmerge(I) obs: 3.273 / Mean I/σ(I) obs: 0.5 / Num. unique obs: 4140 / CC1/2: 0.283 / % possible all: 93.1

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSOct 15, 2015data reduction
Aimless0.5.25data scaling
REFMAC5.8.0049phasing
RefinementResolution: 1.947→39.833 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 1.08 / Phase error: 29.27
RfactorNum. reflection% reflectionSelection details
Rfree0.2347 6549 4.91 %random
Rwork0.1821 ---
obs0.1847 70310 88.43 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.947→39.833 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6721 0 187 617 7525
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077174
X-RAY DIFFRACTIONf_angle_d1.1229769
X-RAY DIFFRACTIONf_dihedral_angle_d14.7852617
X-RAY DIFFRACTIONf_chiral_restr0.041005
X-RAY DIFFRACTIONf_plane_restr0.0051233
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9468-1.9690.5813990.53681566X-RAY DIFFRACTION34
1.969-1.99210.42341940.45362832X-RAY DIFFRACTION60
1.9921-2.01640.43762010.40463555X-RAY DIFFRACTION75
2.0164-2.04190.408720.39051489X-RAY DIFFRACTION31
2.0419-2.06880.51451670.42543814X-RAY DIFFRACTION80
2.0688-2.09710.47171670.40063250X-RAY DIFFRACTION67
2.0971-2.12710.35532370.30944548X-RAY DIFFRACTION96
2.1271-2.15890.3292480.30374609X-RAY DIFFRACTION96
2.1589-2.19260.32092230.3014684X-RAY DIFFRACTION97
2.1926-2.22850.35792150.28154531X-RAY DIFFRACTION96
2.2285-2.26690.42482100.35584182X-RAY DIFFRACTION87
2.2669-2.30820.28732250.24874622X-RAY DIFFRACTION96
2.3082-2.35260.26682250.23564560X-RAY DIFFRACTION96
2.3526-2.40060.26752680.22374579X-RAY DIFFRACTION96
2.4006-2.45280.2942480.22884545X-RAY DIFFRACTION95
2.4528-2.50980.31442710.20784354X-RAY DIFFRACTION91
2.5098-2.57260.26152390.20144614X-RAY DIFFRACTION97
2.5726-2.64210.25922440.19584659X-RAY DIFFRACTION97
2.6421-2.71980.29072620.22224625X-RAY DIFFRACTION97
2.7198-2.80760.2452170.18184628X-RAY DIFFRACTION97
2.8076-2.90790.25692020.18524739X-RAY DIFFRACTION97
2.9079-3.02430.252420.17184570X-RAY DIFFRACTION97
3.0243-3.16190.23652280.16654614X-RAY DIFFRACTION96
3.1619-3.32850.22282380.16524473X-RAY DIFFRACTION94
3.3285-3.53690.21972390.15744697X-RAY DIFFRACTION98
3.5369-3.80980.17422650.13524655X-RAY DIFFRACTION98
3.8098-4.19290.17412340.12524646X-RAY DIFFRACTION97
4.1929-4.79870.15332250.11574646X-RAY DIFFRACTION97
4.7987-6.04250.17842390.13784742X-RAY DIFFRACTION99
6.0425-39.84180.19712050.15624671X-RAY DIFFRACTION97
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)
10.6055-0.15490.1810.85060.29181.54320.009-0.01770.0222-0.0228-0.0558-0.03690.01940.10190.04380.1985-0.04360.04790.26280.02090.2466117.6815250.7221361.4674
20.5243-0.03150.24120.7787-0.08192.43010.01740.03310.0207-0.0262-0.07370.1352-0.0788-0.09420.05160.2380.01710.03050.3198-0.04930.2724115.9446249.2149324.1039
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 302:722)
2X-RAY DIFFRACTION2(chain B and resid 304:721)

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