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- PDB-6pow: Structure of human endotheial nitric oxide synthase heme domain i... -

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Basic information

Entry
Database: PDB / ID: 6pow
TitleStructure of human endotheial nitric oxide synthase heme domain in complex with 7-(5-(Aminomethyl)pyridin-3-yl)-4-methylquinolin-2-amine
ComponentsNitric oxide synthase, endothelial
KeywordsOXIDOREDUCTASE/INHIBITOR / nitric oxide synthase inhibitor / heme enzyme / OXIDOREDUCTASE / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


regulation of the force of heart contraction by chemical signal / NOSIP mediated eNOS trafficking / NOSTRIN mediated eNOS trafficking / negative regulation of muscle hyperplasia / regulation of nervous system process / smooth muscle hyperplasia / response to fluid shear stress / ovulation from ovarian follicle / pulmonary valve morphogenesis / negative regulation of biomineral tissue development ...regulation of the force of heart contraction by chemical signal / NOSIP mediated eNOS trafficking / NOSTRIN mediated eNOS trafficking / negative regulation of muscle hyperplasia / regulation of nervous system process / smooth muscle hyperplasia / response to fluid shear stress / ovulation from ovarian follicle / pulmonary valve morphogenesis / negative regulation of biomineral tissue development / positive regulation of guanylate cyclase activity / Nitric oxide stimulates guanylate cyclase / regulation of systemic arterial blood pressure by endothelin / ROS and RNS production in phagocytes / tetrahydrobiopterin binding / aortic valve morphogenesis / arginine binding / endocardial cushion morphogenesis / ventricular septum morphogenesis / positive regulation of Notch signaling pathway / removal of superoxide radicals / cadmium ion binding / negative regulation of potassium ion transport / negative regulation of platelet activation / negative regulation of calcium ion transport / actin monomer binding / endothelial cell migration / blood vessel remodeling / nitric-oxide synthase (NADPH) / positive regulation of blood vessel endothelial cell migration / nitric-oxide synthase activity / eNOS activation / nitric oxide mediated signal transduction / arginine catabolic process / homeostasis of number of cells within a tissue / regulation of sodium ion transport / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / mitochondrion organization / lipopolysaccharide-mediated signaling pathway / negative regulation of blood pressure / nitric oxide biosynthetic process / blood vessel diameter maintenance / response to hormone / cell redox homeostasis / VEGFR2 mediated vascular permeability / establishment of localization in cell / caveola / negative regulation of smooth muscle cell proliferation / lung development / potassium ion transport / regulation of blood pressure / vasodilation / endocytic vesicle membrane / positive regulation of angiogenesis / calcium ion transport / FMN binding / flavin adenine dinucleotide binding / NADP binding / response to heat / scaffold protein binding / angiogenesis / in utero embryonic development / response to lipopolysaccharide / Extra-nuclear estrogen signaling / calmodulin binding / cytoskeleton / negative regulation of cell population proliferation / Golgi membrane / heme binding / positive regulation of gene expression / Golgi apparatus / 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, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 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, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain 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 / Flavoprotein-like superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
GADOLINIUM ATOM / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-OUA / Nitric oxide synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsChreifi, G. / Li, 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 5, 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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.ptnr1_symmetry / _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 / _struct_conn.ptnr2_symmetry

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)204,88637
Polymers197,3834
Non-polymers7,50333
Water11,241624
1
A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,39118
Polymers98,6922
Non-polymers3,69916
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11320 Å2
ΔGint-154 kcal/mol
Surface area34390 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,49619
Polymers98,6922
Non-polymers3,80417
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9600 Å2
ΔGint-153 kcal/mol
Surface area32920 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.700, 152.710, 108.770
Angle α, β, γ (deg.)90.00, 90.79, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Nitric oxide synthase, endothelial / / Constitutive NOS / cNOS / EC-NOS / Endothelial NOS / eNOS / NOS type III / NOSIII


Mass: 49345.770 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell: endothelial / Gene: NOS3 / Plasmid: pCWori / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P29474, nitric-oxide synthase (NADPH)

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Non-polymers , 9 types, 657 molecules

#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN / Tetrahydrobiopterin


Mass: 241.247 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#4: Chemical
ChemComp-OUA / 7-[5-(aminomethyl)pyridin-3-yl]-4-methylquinolin-2-amine


Mass: 264.325 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C16H16N4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER / Bis-tris methane


Mass: 209.240 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#6: Chemical ChemComp-ZN / ZINC ION


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


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#8: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#9: Chemical
ChemComp-GD / GADOLINIUM ATOM


Mass: 157.250 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Gd
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 624 / 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: 2.69 Å3/Da / Density % sol: 54.3 % / Description: rods
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 10-12% PEG3350, 0.1M BIS-TRIS 0.2-0.3M MG ACETATE, 0.1M GdCl3 10% glycerol, 5 mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: May 28, 2017 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→60 Å / Num. obs: 104668 / % possible obs: 99.2 % / Observed criterion σ(I): -3 / Redundancy: 4.1 % / CC1/2: 0.99 / Rmerge(I) obs: 0.148 / Rpim(I) all: 0.114 / Rsym value: 0.148 / Net I/σ(I): 6
Reflection shellResolution: 2.15→2.21 Å / Redundancy: 4 % / Rmerge(I) obs: 1.328 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 5115 / CC1/2: 0.53 / Rpim(I) all: 1.037 / Rsym value: 1.328 / % possible all: 98.2

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Processing

Software
NameVersionClassification
PHENIX(1.11.1-2575_1496: ???)refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4D1P
Resolution: 2.15→59.694 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 32.47
RfactorNum. reflection% reflectionSelection details
Rfree0.2765 10342 4.99 %random
Rwork0.211 ---
obs0.2142 104570 99.11 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.15→59.694 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12846 0 474 624 13944
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913795
X-RAY DIFFRACTIONf_angle_d1.05118822
X-RAY DIFFRACTIONf_dihedral_angle_d13.538030
X-RAY DIFFRACTIONf_chiral_restr0.0531944
X-RAY DIFFRACTIONf_plane_restr0.0062424
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.17440.37423600.31386441X-RAY DIFFRACTION98
2.1744-2.20.3883390.30876585X-RAY DIFFRACTION98
2.2-2.22680.36433430.29946500X-RAY DIFFRACTION98
2.2268-2.2550.37283370.30616480X-RAY DIFFRACTION99
2.255-2.28470.36753060.3026678X-RAY DIFFRACTION99
2.2847-2.3160.3723710.29026407X-RAY DIFFRACTION98
2.316-2.3490.35063590.28686494X-RAY DIFFRACTION99
2.349-2.38410.31973140.27276598X-RAY DIFFRACTION99
2.3841-2.42140.35043680.26846508X-RAY DIFFRACTION99
2.4214-2.46110.36413640.27176533X-RAY DIFFRACTION99
2.4611-2.50350.37313750.28126504X-RAY DIFFRACTION99
2.5035-2.5490.35763000.26996542X-RAY DIFFRACTION99
2.549-2.59810.31873730.24366630X-RAY DIFFRACTION99
2.5981-2.65110.29483770.23886452X-RAY DIFFRACTION99
2.6511-2.70870.30763710.24226570X-RAY DIFFRACTION99
2.7087-2.77170.32063550.24386526X-RAY DIFFRACTION99
2.7717-2.84110.31063130.2416665X-RAY DIFFRACTION99
2.8411-2.91790.29353790.2316390X-RAY DIFFRACTION99
2.9179-3.00370.32662970.23556667X-RAY DIFFRACTION99
3.0037-3.10070.31373030.22756601X-RAY DIFFRACTION99
3.1007-3.21150.31013350.22766598X-RAY DIFFRACTION99
3.2115-3.34010.29183710.20716591X-RAY DIFFRACTION99
3.3401-3.49210.2463500.19316577X-RAY DIFFRACTION100
3.4921-3.67610.25083540.18566547X-RAY DIFFRACTION100
3.6761-3.90640.23713090.17446664X-RAY DIFFRACTION100
3.9064-4.2080.22283990.16066550X-RAY DIFFRACTION100
4.208-4.63130.21093230.15056598X-RAY DIFFRACTION100
4.6313-5.30110.22573400.15376606X-RAY DIFFRACTION100
5.3011-6.67740.24043540.17726612X-RAY DIFFRACTION100
6.6774-59.71730.20153030.19156640X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
10.17410.01550.00670.0638-0.02420.23730.13890.20650.16770.04350.09120.1261-0.2496-0.29930.39590.38910.11530.10560.2980.17520.279664.361830.8766-185.3211
20.1166-0.02290.04440.1234-0.02310.12240.07470.0412-0.01550.11140.06080.0076-0.0612-0.01310.08490.1667-0.02960.00720.15050.05170.160174.5447.642-157.6369
30.24960.0071-0.0430.0461-0.03280.04070.0497-0.192-0.03310.0385-0.00690.02230.2143-0.0080.03090.5193-0.0047-0.05010.16960.07030.210593.313-34.8439-195.201
40.07960.0406-0.03280.0383-0.01220.10280.0103-0.02340.0015-0.07150.0550.0225-0.00890.062400.1994-0.0081-0.02320.1775-0.00090.1691103.726-11.3171-222.6419
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 68:480)
2X-RAY DIFFRACTION2(chain B and resid 67:480)
3X-RAY DIFFRACTION3(chain C and resid 68:480)
4X-RAY DIFFRACTION4(chain D and resid 67:480)

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