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- PDB-5vv4: Structure of human neuronal nitric oxide synthase heme domain in ... -

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Basic information

Entry
Database: PDB / ID: 5vv4
TitleStructure of human neuronal nitric oxide synthase heme domain in complex with 4-(2-(((2-Aminoquinolin-7-yl)methyl)amino)ethyl)-2-methylbenzonitrile
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/INHIBITOR / nitric oxide synthase / inhibitor complex / heme enzyme / 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 / negative regulation of hydrolase activity / tetrahydrobiopterin binding / regulation of cardiac muscle contraction by calcium ion signaling / arginine binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel ...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 / negative regulation of hydrolase activity / tetrahydrobiopterin binding / regulation of cardiac muscle contraction by calcium ion signaling / arginine binding / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / positive regulation of sodium ion transmembrane transport / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / regulation of cardiac muscle contraction / negative regulation of serotonin uptake / calcium channel regulator activity / nitric-oxide synthase (NADPH) / multicellular organismal response to stress / regulation of ryanodine-sensitive calcium-release channel activity / sodium channel regulator activity / nitric oxide mediated signal transduction / nitric-oxide synthase activity / xenobiotic catabolic process / arginine catabolic process / striated muscle contraction / regulation of sodium ion transport / Ion homeostasis / nitric oxide biosynthetic process / negative regulation of blood pressure / photoreceptor inner segment / response to hormone / cell redox homeostasis / sarcoplasmic reticulum / cell periphery / cellular response to growth factor stimulus / sarcolemma / vasodilation / calcium-dependent protein binding / FMN binding / positive regulation of peptidyl-serine phosphorylation / flavin adenine dinucleotide binding / NADP binding / response to heat / scaffold protein binding / transmembrane transporter binding / response to lipopolysaccharide / dendritic spine / postsynaptic density / cytoskeleton / response to hypoxia / calmodulin binding / 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 / cytosol / cytoplasm
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-9P7 / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsHuiying, L. / Thomas, L.P.
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: Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.
Authors: Pensa, A.V. / Cinelli, M.A. / Li, H. / Chreifi, G. / Mukherjee, P. / Roman, L.J. / Martasek, P. / Poulos, T.L. / Silverman, R.B.
History
DepositionMay 19, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 23, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Dec 25, 2019Group: 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

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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)99,9839
Polymers97,5692
Non-polymers2,4147
Water10,431579
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9320 Å2
ΔGint-84 kcal/mol
Surface area34000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.310, 122.490, 165.190
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
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 , 5 types, 586 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-9P7 / 4-(2-{[(2-aminoquinolin-7-yl)methyl]amino}ethyl)-2-methylbenzonitrile


Mass: 316.400 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H20N4
#5: Chemical ChemComp-ZN / ZINC ION


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


Mass: 18.015 Da / Num. of mol.: 579 / 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: ALS / Beamline: 8.2.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 11, 2015 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→58 Å / Num. obs: 62812 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 4.9 % / CC1/2: 0.995 / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.083 / Rsym value: 0.109 / Net I/σ(I): 9.8
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 5 % / Rmerge(I) obs: 1.179 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 4528 / CC1/2: 0.494 / Rpim(I) all: 0.896 / Rsym value: 1.179 / % possible all: 99.5

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
iMOSFLM0.7.1data reduction
Aimless0.5.8data scaling
REFMAC5.8.0049phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4UH5

4uh5


Resolution: 2.1→57.425 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 0.03 / Phase error: 25.11
RfactorNum. reflection% reflectionSelection details
Rfree0.2194 3066 4.87 %random
Rwork0.1734 ---
obs0.1757 62727 99.75 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.1→57.425 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6692 0 169 579 7440
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077108
X-RAY DIFFRACTIONf_angle_d1.1159680
X-RAY DIFFRACTIONf_dihedral_angle_d14.9092588
X-RAY DIFFRACTIONf_chiral_restr0.07998
X-RAY DIFFRACTIONf_plane_restr0.0051223
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.12390.39971940.32143714X-RAY DIFFRACTION99
2.1239-2.14890.3362100.30483792X-RAY DIFFRACTION99
2.1489-2.17510.31881610.30193845X-RAY DIFFRACTION99
2.1751-2.20260.31821950.29023727X-RAY DIFFRACTION100
2.2026-2.23160.31461830.27783767X-RAY DIFFRACTION100
2.2316-2.26220.35331940.31373802X-RAY DIFFRACTION99
2.2622-2.29450.35971870.26613766X-RAY DIFFRACTION100
2.2945-2.32870.29761730.24973817X-RAY DIFFRACTION100
2.3287-2.36510.28792160.24453762X-RAY DIFFRACTION100
2.3651-2.40390.29322190.22723755X-RAY DIFFRACTION100
2.4039-2.44530.25572050.23193769X-RAY DIFFRACTION100
2.4453-2.48980.2982020.22633788X-RAY DIFFRACTION100
2.4898-2.53770.28092280.21243716X-RAY DIFFRACTION100
2.5377-2.58950.21561960.18933834X-RAY DIFFRACTION100
2.5895-2.64580.2481880.18863731X-RAY DIFFRACTION100
2.6458-2.70730.24872280.19493763X-RAY DIFFRACTION100
2.7073-2.7750.23031630.18733862X-RAY DIFFRACTION100
2.775-2.85010.21271760.1683785X-RAY DIFFRACTION100
2.8501-2.93390.21251940.16883809X-RAY DIFFRACTION100
2.9339-3.02860.20781730.16033812X-RAY DIFFRACTION100
3.0286-3.13690.25482010.17353764X-RAY DIFFRACTION100
3.1369-3.26250.19551770.173877X-RAY DIFFRACTION100
3.2625-3.41090.24951980.15583750X-RAY DIFFRACTION100
3.4109-3.59070.19291960.1493776X-RAY DIFFRACTION100
3.5907-3.81560.17852220.13613763X-RAY DIFFRACTION100
3.8156-4.11020.17152000.12813803X-RAY DIFFRACTION100
4.1102-4.52370.15131940.11633769X-RAY DIFFRACTION100
4.5237-5.17790.16611950.11643822X-RAY DIFFRACTION100
5.1779-6.52210.16471800.14373793X-RAY DIFFRACTION100
6.5221-57.44670.17721650.15323813X-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)
10.6116-0.1387-0.03060.93970.2571.95190.0047-0.00430.0389-0.0474-0.0669-0.00950.08150.09350.06270.1191-0.0170.03010.18630.0330.1924117.3873249.9948361.1457
20.5943-0.1804-0.16640.64490.21773.15340.04650.08140.0187-0.0415-0.0890.0735-0.0514-0.25730.03030.18910.00790.02540.2469-0.02540.222115.9919248.8427323.7681
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 302:721)
2X-RAY DIFFRACTION2(chain B and resid 304:721)

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