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

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Basic information

Entry
Database: PDB / ID: 6ngb
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 6-(3-(3-(dimethylamino)propyl)-2,5-difluorophenethyl)-4-methylpyridin-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 / 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-KMJ / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.9 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: 2019
Title: Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold.
Authors: Do, H.T. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionDec 21, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2019Group: Data collection / 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 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 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

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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)100,0179
Polymers97,5692
Non-polymers2,4487
Water11,331629
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9330 Å2
ΔGint-85 kcal/mol
Surface area33510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.180, 122.510, 164.270
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 BL21(DE3) (bacteria) / References: UniProt: P29475, nitric-oxide synthase (NADPH)

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Non-polymers , 5 types, 636 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-KMJ / 6-(2-{3-[3-(dimethylamino)propyl]-2,5-difluorophenyl}ethyl)-4-methylpyridin-2-amine


Mass: 333.419 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H25F2N3
#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.: 629 / 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: plates
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.2
Details: 8% PEG3350, 35 mM citric acid, 65 mM Bis-Tris propane, 10% glycerol, 5 mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 1.195 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jul 28, 2017 / Details: mirrors
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.195 Å / Relative weight: 1
ReflectionResolution: 1.9→60 Å / Num. obs: 84010 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 5.4 % / CC1/2: 0.997 / Rmerge(I) obs: 0.097 / Rpim(I) all: 0.07 / Rsym value: 0.097 / Net I/σ(I): 8.8
Reflection shellResolution: 1.9→1.95 Å / Redundancy: 5.4 % / Rmerge(I) obs: 1.399 / Mean I/σ(I) obs: 0.9 / Num. unique obs: 4447 / CC1/2: 0.491 / Rpim(I) all: 1.03 / Rsym value: 1.399 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX(1.11.1-2575_1496: ???)refinement
MOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 5AD7

5ad7


Resolution: 1.9→37.775 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 0.02 / Phase error: 24.61
RfactorNum. reflection% reflectionSelection details
Rfree0.2092 7826 4.88 %random
Rwork0.1771 ---
obs0.1787 83885 99.94 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.9→37.775 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6693 0 169 629 7491
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077099
X-RAY DIFFRACTIONf_angle_d0.9489667
X-RAY DIFFRACTIONf_dihedral_angle_d17.8894139
X-RAY DIFFRACTIONf_chiral_restr0.051999
X-RAY DIFFRACTIONf_plane_restr0.0051221
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.92160.39762470.36615128X-RAY DIFFRACTION100
1.9216-1.94420.40742120.35135111X-RAY DIFFRACTION100
1.9442-1.96790.35462740.33065096X-RAY DIFFRACTION100
1.9679-1.99280.33613010.32244985X-RAY DIFFRACTION100
1.9928-2.01910.34142850.30675088X-RAY DIFFRACTION100
2.0191-2.04670.31312330.27895066X-RAY DIFFRACTION100
2.0467-2.0760.31862690.2715141X-RAY DIFFRACTION100
2.076-2.10690.3052760.26185037X-RAY DIFFRACTION100
2.1069-2.13990.28122840.25955040X-RAY DIFFRACTION100
2.1399-2.17490.28232260.24915127X-RAY DIFFRACTION100
2.1749-2.21240.30492530.23545079X-RAY DIFFRACTION100
2.2124-2.25270.25292660.22395094X-RAY DIFFRACTION100
2.2527-2.2960.27292460.21715078X-RAY DIFFRACTION100
2.296-2.34280.25852430.2055103X-RAY DIFFRACTION100
2.3428-2.39380.2493050.1955043X-RAY DIFFRACTION100
2.3938-2.44950.22552720.19625033X-RAY DIFFRACTION100
2.4495-2.51070.22613080.18195083X-RAY DIFFRACTION100
2.5107-2.57860.19812490.16325067X-RAY DIFFRACTION100
2.5786-2.65440.24142800.1695062X-RAY DIFFRACTION100
2.6544-2.74010.20382570.16755132X-RAY DIFFRACTION100
2.7401-2.8380.20422310.16545060X-RAY DIFFRACTION100
2.838-2.95160.16562490.1645106X-RAY DIFFRACTION100
2.9516-3.08580.23132610.16625088X-RAY DIFFRACTION100
3.0858-3.24840.2262420.16265135X-RAY DIFFRACTION100
3.2484-3.45180.18712620.16155034X-RAY DIFFRACTION100
3.4518-3.71820.18652820.1435085X-RAY DIFFRACTION100
3.7182-4.09190.14552750.1375041X-RAY DIFFRACTION100
4.0919-4.68310.15472630.12855100X-RAY DIFFRACTION100
4.6831-5.89660.16622510.14515093X-RAY DIFFRACTION100
5.8966-37.78220.1662240.1535078X-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)
10.6046-0.17560.07731.00010.27651.79290.0190.02420.0229-0.0642-0.058-0.03670.08880.12790.04110.1337-0.01630.03620.18550.0410.1924117.1423250.0453359.0815
20.5793-0.2109-0.02730.71790.11432.95250.03740.02970.00120.0143-0.05880.0904-0.017-0.16650.01080.24040.00430.04130.2631-0.03170.2578115.7604248.7938321.9021
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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