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- PDB-5uob: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 5uob
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with (R)-3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-(2-(methylamino)propyl)benzonitrile
ComponentsNitric oxide synthase, endothelial
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE inhibitor / nitric oxide synthase / inhibitor complex / 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 / negative regulation of muscle hyperplasia / NOSTRIN mediated eNOS trafficking / smooth muscle hyperplasia / regulation of nervous system process / ovulation from ovarian follicle / response to fluid shear stress / pulmonary valve morphogenesis / negative regulation of biomineral tissue development ...regulation of the force of heart contraction by chemical signal / NOSIP mediated eNOS trafficking / negative regulation of muscle hyperplasia / NOSTRIN mediated eNOS trafficking / smooth muscle hyperplasia / regulation of nervous system process / ovulation from ovarian follicle / response to fluid shear stress / 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 / cadmium ion binding / negative regulation of potassium ion transport / negative regulation of calcium ion transport / actin monomer binding / negative regulation of platelet activation / blood vessel remodeling / nitric-oxide synthase (NADPH) / endothelial cell migration / positive regulation of blood vessel endothelial cell migration / nitric oxide mediated signal transduction / nitric-oxide synthase activity / eNOS activation / arginine catabolic process / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / lipopolysaccharide-mediated signaling pathway / regulation of sodium ion transport / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / homeostasis of number of cells within a tissue / nitric oxide biosynthetic process / negative regulation of blood pressure / removal of superoxide radicals / response to hormone / cell redox homeostasis / blood vessel diameter maintenance / VEGFR2 mediated vascular permeability / establishment of localization in cell / mitochondrion organization / negative regulation of smooth muscle cell proliferation / lung development / potassium ion transport / caveola / regulation of blood pressure / vasodilation / positive regulation of angiogenesis / calcium ion transport / endocytic vesicle membrane / 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 / cytoskeleton / calmodulin binding / 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, 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
GADOLINIUM ATOM / PROTOPORPHYRIN IX CONTAINING FE / Chem-M4R / Nitric oxide synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.292 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: J. Med. Chem. / Year: 2017
Title: Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.
Authors: Cinelli, M.A. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionJan 31, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2017Provider: repository / Type: Initial release
Revision 1.1May 24, 2017Group: Database references
Revision 1.2Sep 27, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 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.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

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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)206,38243
Polymers197,3834
Non-polymers8,99939
Water2,000111
1
A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,08621
Polymers98,6922
Non-polymers4,39519
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9940 Å2
ΔGint-191 kcal/mol
Surface area33960 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,29522
Polymers98,6922
Non-polymers4,60420
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10080 Å2
ΔGint-189 kcal/mol
Surface area34200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.534, 153.951, 109.828
Angle α, β, γ (deg.)90.00, 90.57, 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 / Fragment: UNP residues 41-480
Source method: isolated from a genetically manipulated source
Details: Residues 108 to 118 are disordered. The N-terminal residues 41 to 67 are invisible in density.
Source: (gene. exp.) Homo sapiens (human) / Cell line: 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 , 8 types, 150 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-M4R / 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-[(2R)-2-(methylamino)propyl]benzonitrile


Mass: 360.452 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C22H24N4O
#4: 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
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


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


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


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


Mass: 18.015 Da / Num. of mol.: 111 / 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 %
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: Nov 27, 2016 / 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: 2.29→50 Å / Num. obs: 84945 / % possible obs: 99 % / Observed criterion σ(I): -3 / Redundancy: 10.7 % / CC1/2: 0.998 / Rmerge(I) obs: 0.183 / Rpim(I) all: 0.057 / Rsym value: 0.183 / Net I/σ(I): 8.3
Reflection shellResolution: 2.29→2.35 Å / Redundancy: 3.8 % / Rmerge(I) obs: 3.23 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 3703 / CC1/2: 0.346 / Rpim(I) all: 1.811 / Rsym value: 3.23 / % possible all: 82.5

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4D1P

4d1p


Resolution: 2.292→38.488 Å / SU ML: 0.34 / Cross valid method: FREE R-VALUE / σ(F): 0.04 / Phase error: 37.73
RfactorNum. reflection% reflectionSelection details
Rfree0.2788 8210 5 %random
Rwork0.2205 ---
obs0.2234 83250 97.1 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.292→38.488 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12846 0 568 111 13525
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0113898
X-RAY DIFFRACTIONf_angle_d1.19219017
X-RAY DIFFRACTIONf_dihedral_angle_d17.4295042
X-RAY DIFFRACTIONf_chiral_restr0.0761950
X-RAY DIFFRACTIONf_plane_restr0.0062426
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2924-2.31840.40621980.33163506X-RAY DIFFRACTION66
2.3184-2.34570.42712580.32994617X-RAY DIFFRACTION87
2.3457-2.37430.33662300.29814757X-RAY DIFFRACTION88
2.3743-2.40430.36992400.30194902X-RAY DIFFRACTION90
2.4043-2.4360.3753250.2994954X-RAY DIFFRACTION94
2.436-2.46930.39832280.28645127X-RAY DIFFRACTION95
2.4693-2.50460.35243140.28755217X-RAY DIFFRACTION97
2.5046-2.5420.36312810.26745229X-RAY DIFFRACTION99
2.542-2.58170.39342760.26435341X-RAY DIFFRACTION100
2.5817-2.6240.32953140.26795361X-RAY DIFFRACTION100
2.624-2.66920.37882980.28345283X-RAY DIFFRACTION99
2.6692-2.71780.38532820.2935298X-RAY DIFFRACTION99
2.7178-2.770.38563040.26785344X-RAY DIFFRACTION100
2.77-2.82660.35292770.28475336X-RAY DIFFRACTION99
2.8266-2.8880.38142470.2775400X-RAY DIFFRACTION100
2.888-2.95520.37342820.27295314X-RAY DIFFRACTION100
2.9552-3.0290.342920.24555343X-RAY DIFFRACTION100
3.029-3.11090.33392340.23935366X-RAY DIFFRACTION100
3.1109-3.20240.292640.24125421X-RAY DIFFRACTION100
3.2024-3.30570.31612860.2345264X-RAY DIFFRACTION100
3.3057-3.42380.31223020.23985381X-RAY DIFFRACTION100
3.4238-3.56080.30192870.24255360X-RAY DIFFRACTION100
3.5608-3.72270.31842750.24385304X-RAY DIFFRACTION100
3.7227-3.91880.29932780.2215338X-RAY DIFFRACTION100
3.9188-4.1640.24862920.19565323X-RAY DIFFRACTION100
4.164-4.48510.25482790.1815371X-RAY DIFFRACTION100
4.4851-4.93560.20832580.16885391X-RAY DIFFRACTION100
4.9356-5.64790.22163030.18855327X-RAY DIFFRACTION100
5.6479-7.10840.21422710.18715370X-RAY DIFFRACTION100
7.1084-38.49320.18832350.19075378X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 78.8648 Å / Origin y: -1.5765 Å / Origin z: -192.1566 Å
111213212223313233
T0.329 Å2-0.0844 Å2-0.1006 Å2-0.3592 Å2-0.0189 Å2--0.362 Å2
L0.405 °2-0.2563 °2-0.427 °2-0.835 °20.177 °2--1.2113 °2
S0.0911 Å °0.0084 Å °-0.0185 Å °-0.0327 Å °-0.0489 Å °0.0934 Å °-0.1158 Å °-0.0756 Å °-0.0268 Å °
Refinement TLS groupSelection details: all

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