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- PDB-6cif: Structure of the human endothelial nitric oxide synthase heme dom... -

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Basic information

Entry
Database: PDB / ID: 6cif
TitleStructure of the human endothelial nitric oxide synthase heme domain in complex with N-(1-(Piperidin-4-yl)indolin-5-yl)thiophene-2-carboximidamide
ComponentsNitric oxide synthase, endothelial
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor complex heme enzyme
Function / homology
Function and homology information


negative regulation of muscle hyperplasia / regulation of the force of heart contraction by chemical signal / NOSIP mediated eNOS trafficking / tetrahydrobiopterin metabolic process / NOSTRIN mediated eNOS trafficking / smooth muscle hyperplasia / regulation of nervous system process / superoxide-generating NAD(P)H oxidase activity / : / ovulation from ovarian follicle ...negative regulation of muscle hyperplasia / regulation of the force of heart contraction by chemical signal / NOSIP mediated eNOS trafficking / tetrahydrobiopterin metabolic process / NOSTRIN mediated eNOS trafficking / smooth muscle hyperplasia / regulation of nervous system process / superoxide-generating NAD(P)H oxidase activity / : / ovulation from ovarian follicle / pulmonary valve morphogenesis / response to fluid shear stress / positive regulation of guanylate cyclase activity / negative regulation of biomineral tissue development / Nitric oxide stimulates guanylate cyclase / regulation of systemic arterial blood pressure by endothelin / ROS and RNS production in phagocytes / tetrahydrobiopterin binding / arginine binding / aortic valve morphogenesis / endocardial cushion morphogenesis / ventricular septum morphogenesis / positive regulation of Notch signaling pathway / cadmium ion binding / negative regulation of potassium ion transport / negative regulation of calcium ion transport / nitric oxide mediated signal transduction / negative regulation of platelet activation / actin monomer binding / blood vessel remodeling / nitric-oxide synthase (NADPH) / positive regulation of blood vessel endothelial cell migration / nitric-oxide synthase activity / endothelial cell migration / L-arginine catabolic process / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / regulation of sodium ion transport / eNOS activation / nitric oxide metabolic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / negative regulation of blood pressure / homeostasis of number of cells within a tissue / response to hormone / nitric oxide biosynthetic process / removal of superoxide radicals / cell redox homeostasis / lipopolysaccharide-mediated signaling pathway / blood vessel diameter maintenance / VEGFR2 mediated vascular permeability / mitochondrion organization / establishment of localization in cell / negative regulation of smooth muscle cell proliferation / lung development / potassium ion transport / caveola / regulation of blood pressure / positive regulation of angiogenesis / calcium ion transport / vasodilation / endocytic vesicle membrane / FMN binding / flavin adenine dinucleotide binding / NADP binding / response to heat / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / scaffold protein binding / angiogenesis / response to lipopolysaccharide / in utero embryonic development / cytoskeleton / Extra-nuclear estrogen signaling / calmodulin binding / Golgi membrane / negative regulation of cell population proliferation / 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, 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 / Flavoprotein-like superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-F2J / GADOLINIUM ATOM / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsChreifi, G. / Li, 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: Biochemistry / Year: 2018
Title: Structural Basis for Isoform Selective Nitric Oxide Synthase Inhibition by Thiophene-2-carboximidamides.
Authors: Li, H. / Evenson, R.J. / Chreifi, G. / Silverman, R.B. / Poulos, T.L.
History
DepositionFeb 23, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 31, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 7, 2018Group: Data collection / Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.identifier_ORCID
Revision 1.2Nov 21, 2018Group: 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 1.3Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 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 / 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.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.ptnr2_symmetry / _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.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.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)205,49939
Polymers197,3834
Non-polymers8,11635
Water10,178565
1
A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,64519
Polymers98,6922
Non-polymers3,95317
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11070 Å2
ΔGint-146 kcal/mol
Surface area34380 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,85420
Polymers98,6922
Non-polymers4,16318
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10870 Å2
ΔGint-145 kcal/mol
Surface area33510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.789, 152.579, 108.690
Angle α, β, γ (deg.)90.00, 90.81, 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 (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P29474, nitric-oxide synthase (NADPH)

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Non-polymers , 9 types, 600 molecules

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


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


Mass: 241.247 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#4: Chemical
ChemComp-F2J / N-[1-(piperidin-4-yl)-1H-indol-5-yl]thiophene-2-carboximidamide


Mass: 324.443 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H20N4S
#5: Chemical
ChemComp-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER


Mass: 209.240 Da / Num. of mol.: 11 / 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


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


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


Mass: 18.015 Da / Num. of mol.: 565 / 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: 2.69 Å3/Da / Density % sol: 54.3 % / Description: rods
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 12-15% 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
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 18, 2017 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 94161 / % possible obs: 95.7 % / Observed criterion σ(I): -3 / Redundancy: 5 % / CC1/2: 0.989 / Rmerge(I) obs: 0.212 / Rpim(I) all: 0.154 / Rsym value: 0.212 / Net I/σ(I): 7
Reflection shellResolution: 2.2→2.26 Å / Redundancy: 4.8 % / Rmerge(I) obs: 2.798 / Num. unique obs: 4645 / CC1/2: 0.231 / Rpim(I) all: 2.093 / Rsym value: 2.798 / % possible all: 95.9

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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: 4DIP

4dip


Resolution: 2.2→46.065 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 27.89 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2456 4713 5 %random
Rwork0.1888 ---
obs0.1916 94090 94.08 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.2→46.065 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12877 0 508 565 13950
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913850
X-RAY DIFFRACTIONf_angle_d1.1518891
X-RAY DIFFRACTIONf_dihedral_angle_d15.0168118
X-RAY DIFFRACTIONf_chiral_restr0.0531960
X-RAY DIFFRACTIONf_plane_restr0.0062432
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.2250.34082930.29315779X-RAY DIFFRACTION94
2.225-2.25120.35493280.29525824X-RAY DIFFRACTION95
2.2512-2.27860.33672400.2855665X-RAY DIFFRACTION90
2.2786-2.30750.36312930.29535188X-RAY DIFFRACTION83
2.3075-2.33780.34633430.28775711X-RAY DIFFRACTION95
2.3378-2.36990.34682770.2675997X-RAY DIFFRACTION96
2.3699-2.40370.30823290.25985874X-RAY DIFFRACTION95
2.4037-2.43960.34422990.25035941X-RAY DIFFRACTION97
2.4396-2.47770.30533510.25036015X-RAY DIFFRACTION97
2.4777-2.51830.32893180.24255896X-RAY DIFFRACTION96
2.5183-2.56180.28862750.24395975X-RAY DIFFRACTION96
2.5618-2.60830.30023620.23055805X-RAY DIFFRACTION94
2.6083-2.65850.27443300.21855807X-RAY DIFFRACTION95
2.6585-2.71280.30553340.22585822X-RAY DIFFRACTION94
2.7128-2.77170.27463050.22395496X-RAY DIFFRACTION90
2.7717-2.83620.28952420.22815345X-RAY DIFFRACTION86
2.8362-2.90710.25313620.20435865X-RAY DIFFRACTION97
2.9071-2.98570.31072930.20266017X-RAY DIFFRACTION96
2.9857-3.07350.27962630.19565969X-RAY DIFFRACTION97
3.0735-3.17270.26222750.20155929X-RAY DIFFRACTION95
3.1727-3.28610.28013390.19535947X-RAY DIFFRACTION97
3.2861-3.41760.23243200.17885888X-RAY DIFFRACTION96
3.4176-3.57310.22713200.1645804X-RAY DIFFRACTION94
3.5731-3.76140.21772900.15585370X-RAY DIFFRACTION87
3.7614-3.99690.19962970.14856117X-RAY DIFFRACTION98
3.9969-4.30530.18843240.13946007X-RAY DIFFRACTION98
4.3053-4.73820.17132940.12895984X-RAY DIFFRACTION97
4.7382-5.42290.21372960.14565580X-RAY DIFFRACTION90
5.4229-6.82870.21553030.15955877X-RAY DIFFRACTION96
6.8287-46.0750.16692760.17375762X-RAY DIFFRACTION93
Refinement TLS params.Method: refined / Origin x: -49.3201 Å / Origin y: -0.0703 Å / Origin z: -190.2025 Å
111213212223313233
T0.2011 Å2-0.0489 Å20.035 Å2-0.2113 Å2-0.0375 Å2--0.2155 Å2
L0.2479 °2-0.1533 °20.2876 °2-0.2696 °2-0.197 °2--0.6907 °2
S0.0534 Å °-0.0072 Å °-0.0245 Å °-0.0258 Å °-0.001 Å °-0.0175 Å °0.0332 Å °0.0108 Å °-0.0373 Å °
Refinement TLS groupSelection details: all

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