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

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Basic information

Entry
Database: PDB / ID: 6auy
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 4-Methyl-6-(3-(3-(methylamino)propyl)phenethyl)pyridin-2-amine
ComponentsNitric oxide synthase, brain
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor complex heme enzyme
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) / sodium channel regulator activity / regulation of ryanodine-sensitive calcium-release channel activity / nitric oxide mediated signal transduction / nitric-oxide synthase activity / xenobiotic catabolic process / multicellular organismal response to stress / 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 / sarcolemma / cellular response to growth factor stimulus / 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 / calmodulin binding / response to hypoxia / 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-BYJ / 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: 1.92 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: Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker.
Authors: Do, H.T. / Wang, H.Y. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionSep 1, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 11, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
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)100,28513
Polymers97,5692
Non-polymers2,71611
Water8,503472
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10280 Å2
ΔGint-85 kcal/mol
Surface area34180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.515, 122.031, 165.106
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 344 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, 483 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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-BYJ / 4-methyl-6-(2-{3-[3-(methylamino)propyl]phenyl}ethyl)pyridin-2-amine


Mass: 283.411 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H25N3
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 472 / 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: Mar 19, 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: 1.92→50 Å / Num. obs: 81949 / % possible obs: 99.8 % / Observed criterion σ(I): -3 / Redundancy: 5.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.107 / Rsym value: 0.107 / Net I/σ(I): 8.8
Reflection shellResolution: 1.92→1.97 Å / Redundancy: 5.8 % / Rmerge(I) obs: 5.091 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 4319 / CC1/2: 0.357 / % possible all: 96.9

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSOct 15, 2015data reduction
Aimless0.5.17data scaling
REFMAC5.8.0049phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4UH5

4uh5


Resolution: 1.92→39.1 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 1.18 / Phase error: 31.66
RfactorNum. reflection% reflectionSelection details
Rfree0.2356 3778 4.89 %random
Rwork0.1861 ---
obs0.1885 77143 93.79 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.92→39.1 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6715 0 187 472 7374
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077129
X-RAY DIFFRACTIONf_angle_d1.1199695
X-RAY DIFFRACTIONf_dihedral_angle_d15.2142598
X-RAY DIFFRACTIONf_chiral_restr0.039999
X-RAY DIFFRACTIONf_plane_restr0.0041223
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9202-1.9420.4209780.50931937X-RAY DIFFRACTION38
1.942-1.96490.53471170.45462562X-RAY DIFFRACTION52
1.9649-1.98880.46232110.43533360X-RAY DIFFRACTION68
1.9888-2.0140.4412230.40994160X-RAY DIFFRACTION83
2.014-2.04050.42832410.3864553X-RAY DIFFRACTION92
2.0405-2.06850.40232190.36514399X-RAY DIFFRACTION89
2.0685-2.0980.39472700.35954909X-RAY DIFFRACTION98
2.098-2.12930.39222590.34734825X-RAY DIFFRACTION100
2.1293-2.16260.35592570.32944953X-RAY DIFFRACTION99
2.1626-2.19810.3612350.32764969X-RAY DIFFRACTION99
2.1981-2.23590.35562370.31064920X-RAY DIFFRACTION99
2.2359-2.27660.34622490.30144979X-RAY DIFFRACTION99
2.2766-2.32040.35772360.26964920X-RAY DIFFRACTION100
2.3204-2.36770.29672730.24064965X-RAY DIFFRACTION100
2.3677-2.41920.30032630.23614900X-RAY DIFFRACTION100
2.4192-2.47550.27762720.24074964X-RAY DIFFRACTION100
2.4755-2.53740.29332880.21564892X-RAY DIFFRACTION100
2.5374-2.6060.26172560.19994961X-RAY DIFFRACTION100
2.606-2.68260.25432810.19844883X-RAY DIFFRACTION100
2.6826-2.76920.23642280.19995042X-RAY DIFFRACTION100
2.7692-2.86820.24852260.1984933X-RAY DIFFRACTION100
2.8682-2.98290.2692570.19034951X-RAY DIFFRACTION100
2.9829-3.11870.24752400.18145008X-RAY DIFFRACTION100
3.1187-3.2830.23022400.18214933X-RAY DIFFRACTION100
3.283-3.48860.23142510.16644986X-RAY DIFFRACTION100
3.4886-3.75770.20132850.14444916X-RAY DIFFRACTION100
3.7577-4.13550.18392640.13014927X-RAY DIFFRACTION100
4.1355-4.7330.16012570.1214954X-RAY DIFFRACTION100
4.733-5.95970.1752460.13544956X-RAY DIFFRACTION100
5.9597-39.10840.18212200.14894979X-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)
10.9215-0.2553-0.20241.04530.28653.1319-0.0058-0.05420.0078-0.0415-0.0801-0.04040.1930.16290.08340.2213-0.02150.03660.31810.05150.2996117.9751249.2023361.0788
20.7205-0.2634-0.39590.98120.29314.87430.05120.1485-0.0277-0.0824-0.10770.1070.013-0.38820.03620.25530.00440.02460.3847-0.0370.2914116.4671247.735323.7128
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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