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- PDB-6av3: Structure of human neuronal nitric oxide synthase R354A/G357D mut... -

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Basic information

Entry
Database: PDB / ID: 6av3
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 4-Methyl-6-(2-(5-(3-((methylamino)methyl)phenyl)pyridin-3-yl)ethyl)pyridin-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 / peptidyl-cysteine S-nitrosylase activity / Nitric oxide stimulates guanylate cyclase / myoblast fusion / ROS and RNS production in phagocytes / 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 / peptidyl-cysteine S-nitrosylase activity / Nitric oxide stimulates guanylate cyclase / myoblast fusion / ROS and RNS production in phagocytes / 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 / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of potassium ion transport / negative regulation of calcium ion transport / nitric oxide mediated signal transduction / sodium channel regulator activity / nitric-oxide synthase (NADPH) / negative regulation of serotonin uptake / calcium channel regulator activity / regulation of cardiac muscle contraction / nitric-oxide synthase activity / multicellular organismal response to stress / xenobiotic catabolic process / arginine catabolic process / striated muscle contraction / regulation of sodium ion transport / Ion homeostasis / negative regulation of blood pressure / response to hormone / photoreceptor inner segment / nitric oxide biosynthetic process / cell redox homeostasis / sarcoplasmic reticulum / cell periphery / sarcolemma / cellular response to growth factor stimulus / vasodilation / calcium-dependent protein binding / FMN binding / NADP binding / flavin adenine dinucleotide binding / response to heat / scaffold protein binding / response to lipopolysaccharide / dendritic spine / transmembrane transporter binding / response to hypoxia / cytoskeleton / calmodulin binding / 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 / 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-W79 / Nitric oxide synthase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.95 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 1.2Jan 1, 2020Group: 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)100,0159
Polymers97,5692
Non-polymers2,4467
Water6,071337
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9320 Å2
ΔGint-85 kcal/mol
Surface area33630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.490, 122.247, 163.994
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
Source method: isolated from a genetically manipulated source
Details: Residues 344 to 351 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 , 5 types, 344 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-W79 / 4-methyl-6-[2-(5-{3-[(methylamino)methyl]phenyl}pyridin-3-yl)ethyl]pyridin-2-amine


Mass: 332.442 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H24N4
#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.: 337 / 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 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: 0.9794 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 26, 2016 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9794 Å / Relative weight: 1
ReflectionResolution: 1.95→60 Å / Num. obs: 77910 / % possible obs: 99.4 % / Observed criterion σ(I): -3 / Redundancy: 5.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.131 / Rpim(I) all: 0.058 / Rsym value: 0.131 / Net I/σ(I): 6.8
Reflection shellResolution: 1.95→2.01 Å / Redundancy: 5.5 % / Rmerge(I) obs: 4.078 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 4441 / CC1/2: 0.556 / Rpim(I) all: 1.855 / Rsym value: 4.078 / % possible all: 97.3

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Processing

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

4uh5


Resolution: 1.95→38.871 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.14 / Phase error: 35.96
RfactorNum. reflection% reflectionSelection details
Rfree0.2589 3677 4.92 %random
Rwork0.2026 ---
obs0.2053 74663 95.07 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.95→38.871 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6693 0 171 337 7201
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077096
X-RAY DIFFRACTIONf_angle_d1.0969660
X-RAY DIFFRACTIONf_dihedral_angle_d15.3092576
X-RAY DIFFRACTIONf_chiral_restr0.04996
X-RAY DIFFRACTIONf_plane_restr0.0051221
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9466-1.96880.56571390.50282426X-RAY DIFFRACTION52
1.9688-1.99190.48422020.4673397X-RAY DIFFRACTION72
1.9919-2.01620.47122240.43744046X-RAY DIFFRACTION85
2.0162-2.04170.47131950.43783938X-RAY DIFFRACTION84
2.0417-2.06860.43532050.40144291X-RAY DIFFRACTION91
2.0686-2.09690.43622690.38014608X-RAY DIFFRACTION96
2.0969-2.12690.38262520.36954576X-RAY DIFFRACTION99
2.1269-2.15860.36362400.35914670X-RAY DIFFRACTION99
2.1586-2.19240.41312280.3374747X-RAY DIFFRACTION99
2.1924-2.22830.40362260.32444648X-RAY DIFFRACTION99
2.2283-2.26670.37382120.33264711X-RAY DIFFRACTION99
2.2667-2.30790.38682450.29414656X-RAY DIFFRACTION99
2.3079-2.35230.37192440.29364676X-RAY DIFFRACTION99
2.3523-2.40030.33882660.27354714X-RAY DIFFRACTION99
2.4003-2.45250.34952460.27384620X-RAY DIFFRACTION99
2.4525-2.50950.29182760.2534489X-RAY DIFFRACTION96
2.5095-2.57230.29212250.23464651X-RAY DIFFRACTION99
2.5723-2.64180.28132610.22464715X-RAY DIFFRACTION99
2.6418-2.71950.28192520.22044673X-RAY DIFFRACTION99
2.7195-2.80730.29382160.21514707X-RAY DIFFRACTION99
2.8073-2.90760.27472170.20924756X-RAY DIFFRACTION99
2.9076-3.0240.27442320.20384695X-RAY DIFFRACTION99
3.024-3.16150.27312420.21824684X-RAY DIFFRACTION99
3.1615-3.32810.26572430.20424661X-RAY DIFFRACTION98
3.3281-3.53650.23982420.17234740X-RAY DIFFRACTION100
3.5365-3.80940.19962670.16184703X-RAY DIFFRACTION100
3.8094-4.19230.21562420.13644681X-RAY DIFFRACTION99
4.1923-4.7980.17112280.12424673X-RAY DIFFRACTION98
4.798-6.04130.18372380.13954724X-RAY DIFFRACTION100
6.0413-38.87850.18932100.14794731X-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)
11.1019-0.1966-0.40511.20840.51164.8707-0.0141-0.1181-0.0035-0.0424-0.0507-0.03980.36870.25760.05910.2142-0.01110.02160.39340.05320.2773117.7888249.3913358.523
21.0063-0.2545-0.67711.1780.40457.06510.03930.2511-0.0318-0.1394-0.09820.06840.1591-0.38150.03580.3030.0090.00830.4635-0.0330.2871116.5605248.2751321.4622
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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