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- PDB-6pnf: Structure of human neuronal nitric oxide synthase R354A/G357D mut... -

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Basic information

Entry
Database: PDB / ID: 6pnf
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 7-(3-(Aminomethyl)-4-ethoxyphenyl)-4-methylquinolin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE/Inhibitor / nitric oxide synthase inhibitor / 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 / 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
5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-OSJ / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsLi, H. / Poulos, T.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)GM57353 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.
Authors: Cinelli, M.A. / Reidl, C.T. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionJul 2, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1May 27, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 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

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)100,05710
Polymers97,5692
Non-polymers2,4888
Water8,035446
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9470 Å2
ΔGint-83 kcal/mol
Surface area34120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.070, 124.460, 165.300
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 / 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 BL21(DE3) (bacteria) / References: UniProt: P29475, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 454 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-OSJ / 7-[3-(aminomethyl)-4-ethoxyphenyl]-4-methylquinolin-2-amine


Mass: 307.390 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H21N3O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 446 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: plates
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 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 1.127 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Feb 19, 2017 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.127 Å / Relative weight: 1
ReflectionResolution: 2.1→60 Å / Num. obs: 60754 / % possible obs: 95.7 % / Observed criterion σ(I): -3 / Redundancy: 3.8 % / CC1/2: 0.994 / Rmerge(I) obs: 0.105 / Rpim(I) all: 0.093 / Rsym value: 0.105 / Net I/σ(I): 5.1
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 3.7 % / Rmerge(I) obs: 1.525 / Mean I/σ(I) obs: 0.6 / Num. unique obs: 3828 / CC1/2: 0.5 / Rpim(I) all: 1.344 / Rsym value: 1.525 / % possible all: 86.6

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
MOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4UH5

4uh5


Resolution: 2.1→46.127 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 0.25 / Phase error: 29.15
RfactorNum. reflection% reflectionSelection details
Rfree0.2429 5392 4.87 %random
Rwork0.1855 ---
obs0.1883 60663 91.38 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.1→46.127 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6699 0 173 446 7318
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0087103
X-RAY DIFFRACTIONf_angle_d1.1199671
X-RAY DIFFRACTIONf_dihedral_angle_d15.7972578
X-RAY DIFFRACTIONf_chiral_restr0.04997
X-RAY DIFFRACTIONf_plane_restr0.0051220
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.12390.36321740.34493094X-RAY DIFFRACTION81
2.1239-2.14880.3551790.32543064X-RAY DIFFRACTION80
2.1488-2.17510.36461550.32813088X-RAY DIFFRACTION79
2.1751-2.20260.34671270.31273147X-RAY DIFFRACTION82
2.2026-2.23160.37751610.30653153X-RAY DIFFRACTION82
2.2316-2.26210.35741540.30493210X-RAY DIFFRACTION82
2.2621-2.29450.35931680.29193257X-RAY DIFFRACTION85
2.2945-2.32870.35261600.27853269X-RAY DIFFRACTION86
2.3287-2.36510.32871720.27163322X-RAY DIFFRACTION86
2.3651-2.40390.29311910.26593362X-RAY DIFFRACTION88
2.4039-2.44530.31331930.27483444X-RAY DIFFRACTION90
2.4453-2.48980.34461900.27193471X-RAY DIFFRACTION91
2.4898-2.53770.32311930.25933464X-RAY DIFFRACTION91
2.5377-2.58950.29491880.23513595X-RAY DIFFRACTION93
2.5895-2.64580.32061970.22913532X-RAY DIFFRACTION94
2.6458-2.70730.32872010.23433631X-RAY DIFFRACTION94
2.7073-2.7750.26451740.22413648X-RAY DIFFRACTION96
2.775-2.850.30791640.21193713X-RAY DIFFRACTION96
2.85-2.93390.25991730.20843727X-RAY DIFFRACTION97
2.9339-3.02850.30481940.20343701X-RAY DIFFRACTION97
3.0285-3.13680.23621870.20683747X-RAY DIFFRACTION97
3.1368-3.26230.25631800.19443774X-RAY DIFFRACTION97
3.2623-3.41070.26041830.17223704X-RAY DIFFRACTION97
3.4107-3.59050.24242000.17283704X-RAY DIFFRACTION97
3.5905-3.81540.2052180.15553735X-RAY DIFFRACTION97
3.8154-4.10980.21331860.14033761X-RAY DIFFRACTION97
4.1098-4.5230.20362020.13083731X-RAY DIFFRACTION98
4.523-5.17680.1721890.12943771X-RAY DIFFRACTION97
5.1768-6.51920.18951790.1633765X-RAY DIFFRACTION98
6.5192-46.13840.1961600.15723742X-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)
10.6835-0.18020.04230.87180.10162.07830.0353-0.0090.0230.0029-0.1213-0.03930.10860.04550.07650.2738-0.06610.0410.31260.02970.3306117.1869253.9113362.0535
20.4968-0.0392-0.06050.75580.1643.03640.0130.0089-0.0458-0.0163-0.08470.09480.0807-0.22390.05590.2809-0.01410.02070.3454-0.03930.3483115.3807252.4914324.6088
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 302:722 )A302 - 722
2X-RAY DIFFRACTION2( CHAIN B AND RESID 304:721 )B304 - 721

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