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

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Basic information

Entry
Database: PDB / ID: 6pna
TitleStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 7-(4-(2-Aminoethyl)phenyl)-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 / tetrahydrobiopterin binding / arginine binding / regulation of cardiac muscle contraction by calcium ion signaling / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / synaptic signaling by nitric oxide ...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 / tetrahydrobiopterin binding / arginine binding / regulation of cardiac muscle contraction by calcium ion signaling / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / synaptic signaling by nitric oxide / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of sodium ion transmembrane transport / peptidyl-cysteine S-nitrosylase activity / cadmium ion binding / positive regulation of the force of heart contraction / negative regulation of calcium ion transport / negative regulation of potassium ion transport / regulation of postsynaptic membrane potential / nitric oxide mediated signal transduction / nitric-oxide synthase (NADPH) / sodium channel regulator activity / negative regulation of serotonin uptake / regulation of neurogenesis / regulation of cardiac muscle contraction / nitric-oxide synthase activity / multicellular organismal response to stress / xenobiotic catabolic process / L-arginine catabolic process / striated muscle contraction / regulation of sodium ion transport / negative regulation of blood pressure / Ion homeostasis / response to hormone / nitric oxide biosynthetic process / photoreceptor inner segment / T-tubule / sarcoplasmic reticulum membrane / cell redox homeostasis / calyx of Held / sarcoplasmic reticulum / cell periphery / calcium channel regulator activity / establishment of localization in cell / sarcolemma / caveola / cellular response to growth factor stimulus / potassium ion transport / vasodilation / Z disc / calcium-dependent protein binding / calcium ion transport / FMN binding / flavin adenine dinucleotide binding / NADP binding / positive regulation of neuron apoptotic process / response to heat / scaffold protein binding / response to lipopolysaccharide / dendritic spine / transmembrane transporter binding / cytoskeleton / calmodulin binding / response to hypoxia / 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 / cytoplasm / cytosol
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 / PDZ 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 / 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-M16 / 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 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)99,99710
Polymers97,5692
Non-polymers2,4288
Water13,475748
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9580 Å2
ΔGint-86 kcal/mol
Surface area34330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.050, 122.250, 164.640
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, 756 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
#4: Chemical ChemComp-M16 / 7-[4-(2-aminoethyl)phenyl]-4-methylquinolin-2-amine


Mass: 277.364 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H19N3
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#6: Chemical ChemComp-ZN / ZINC ION


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


Mass: 18.015 Da / Num. of mol.: 748 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 0.9795 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Jan 22, 2017 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.95→60 Å / Num. obs: 76617 / % possible obs: 99 % / Observed criterion σ(I): -3 / Redundancy: 4 % / CC1/2: 0.989 / Rmerge(I) obs: 0.141 / Rpim(I) all: 0.121 / Rsym value: 0.141 / Net I/σ(I): 5.3
Reflection shellResolution: 1.95→2.01 Å / Redundancy: 3.9 % / Rmerge(I) obs: 2.087 / Mean I/σ(I) obs: 0.7 / Num. unique obs: 4364 / CC1/2: 0.315 / Rpim(I) all: 1.843 / Rsym value: 2.087 / % possible all: 97

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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: 1.95→43.993 Å / SU ML: 0.31 / Cross valid method: FREE R-VALUE / σ(F): 0.03 / Phase error: 29.17
RfactorNum. reflection% reflectionSelection details
Rfree0.2436 7046 4.92 %random
Rwork0.1947 ---
obs0.1971 76483 96.84 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.95→43.993 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6724 0 169 748 7641
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0077143
X-RAY DIFFRACTIONf_angle_d1.1139728
X-RAY DIFFRACTIONf_dihedral_angle_d15.2322602
X-RAY DIFFRACTIONf_chiral_restr0.0421003
X-RAY DIFFRACTIONf_plane_restr0.0051229
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.97220.43392500.3814392X-RAY DIFFRACTION95
1.9722-1.99540.40572780.36854382X-RAY DIFFRACTION93
1.9954-2.01970.38532370.36264386X-RAY DIFFRACTION95
2.0197-2.04530.34662180.33854547X-RAY DIFFRACTION96
2.0453-2.07220.38652240.33044473X-RAY DIFFRACTION94
2.0722-2.10060.33642280.31924443X-RAY DIFFRACTION96
2.1006-2.13060.35782700.30914452X-RAY DIFFRACTION96
2.1306-2.16240.32692040.30394570X-RAY DIFFRACTION95
2.1624-2.19620.36492250.28924519X-RAY DIFFRACTION97
2.1962-2.23220.3072140.27574621X-RAY DIFFRACTION97
2.2322-2.27070.31362270.27444587X-RAY DIFFRACTION97
2.2707-2.31190.32032390.25334484X-RAY DIFFRACTION98
2.3119-2.35640.28692560.24164648X-RAY DIFFRACTION97
2.3564-2.40450.27132540.23374500X-RAY DIFFRACTION97
2.4045-2.45680.27872530.23144586X-RAY DIFFRACTION98
2.4568-2.51390.29992480.22094520X-RAY DIFFRACTION98
2.5139-2.57680.28612420.21314634X-RAY DIFFRACTION98
2.5768-2.64640.28742510.21324552X-RAY DIFFRACTION98
2.6464-2.72430.25122380.20854600X-RAY DIFFRACTION98
2.7243-2.81220.25592170.1974631X-RAY DIFFRACTION98
2.8122-2.91270.22432040.18434648X-RAY DIFFRACTION98
2.9127-3.02930.22922190.18044625X-RAY DIFFRACTION98
3.0293-3.16710.26952290.18364559X-RAY DIFFRACTION98
3.1671-3.33410.24672450.16414599X-RAY DIFFRACTION98
3.3341-3.54290.2192380.15744592X-RAY DIFFRACTION98
3.5429-3.81630.18192530.14194549X-RAY DIFFRACTION97
3.8163-4.20010.17462420.13094489X-RAY DIFFRACTION97
4.2001-4.80720.1572040.12664359X-RAY DIFFRACTION92
4.8072-6.0540.18562330.1444622X-RAY DIFFRACTION99
6.054-44.00460.18512060.16034618X-RAY DIFFRACTION98
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)
10.6968-0.16780.01890.81120.21111.69470.03050.01920.02-0.0368-0.0531-0.02780.00750.11950.01940.1611-0.01550.02460.20130.03090.2038116.898249.6207359.9256
20.4917-0.145-0.00390.68350.03352.62760.04380.0560.0081-0.0048-0.04960.0455-0.0285-0.10480.00080.18350.00880.02710.2305-0.01970.2147115.3429248.2218322.6028
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 302:722)
2X-RAY DIFFRACTION2(chain B and resid 304:722)

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