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- PDB-5uo9: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 5uo9
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with 7-[(3-Ethyl-5-((methylamino)methyl)phenoxy)methyl]quinolin-2-amine
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 / 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 ...regulation of the force of heart contraction by chemical signal / NOSIP mediated eNOS trafficking / negative regulation of muscle hyperplasia / 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 / 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 calcium ion transport / negative regulation of potassium ion transport / negative regulation of platelet activation / actin monomer binding / nitric oxide mediated signal transduction / nitric-oxide synthase (NADPH) / blood vessel remodeling / 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 / negative regulation of blood pressure / response to hormone / nitric oxide metabolic process / eNOS activation / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / nitric oxide biosynthetic process / homeostasis of number of cells within a tissue / removal of superoxide radicals / lung development / cell redox homeostasis / lipopolysaccharide-mediated signaling pathway / blood vessel diameter maintenance / VEGFR2 mediated vascular permeability / mitochondrion organization / negative regulation of smooth muscle cell proliferation / establishment of localization in cell / caveola / potassium ion transport / regulation of blood pressure / vasodilation / positive regulation of angiogenesis / endocytic vesicle membrane / calcium ion transport / FMN binding / NADP binding / flavin adenine dinucleotide binding / response to heat / scaffold protein binding / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / angiogenesis / response to lipopolysaccharide / in utero embryonic development / cytoskeleton / calmodulin binding / Extra-nuclear estrogen signaling / Golgi membrane / negative regulation of cell population proliferation / heme binding / positive regulation of gene expression / Golgi apparatus / 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 / 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-8J4 / 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: 2.19 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.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.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)205,79643
Polymers197,3834
Non-polymers8,41339
Water6,954386
1
A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,30723
Polymers98,6922
Non-polymers4,61521
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11210 Å2
ΔGint-147 kcal/mol
Surface area34290 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,48920
Polymers98,6922
Non-polymers3,79818
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11320 Å2
ΔGint-168 kcal/mol
Surface area33090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.376, 152.087, 108.219
Angle α, β, γ (deg.)90.00, 90.59, 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 110 to 118 are disordered. The N-terminal residues 41 to 67 are invisible in density.
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 , 11 types, 425 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
#4: Chemical
ChemComp-8J4 / 7-({3-ethyl-5-[(methylamino)methyl]phenoxy}methyl)quinolin-2-amine


Mass: 321.416 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H23N3O
#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.: 12 / 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.: 5 / 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: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#11: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#12: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 386 / 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: 0.9795 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 4, 2016 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.19→50 Å / Num. obs: 95528 / % possible obs: 96.9 % / Observed criterion σ(I): -3 / Redundancy: 6.3 % / CC1/2: 0.996 / Rmerge(I) obs: 0.161 / Rpim(I) all: 0.069 / Rsym value: 0.161 / Net I/σ(I): 7.8
Reflection shellResolution: 2.19→2.25 Å / Redundancy: 5.6 % / Rmerge(I) obs: 3.613 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 4367 / CC1/2: 0.231 / Rpim(I) all: 1.6 / Rsym value: 3.613 / % possible all: 90

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Processing

Software
NameVersionClassification
PHENIX1.8.2_1309refinement
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4D1P

4d1p


Resolution: 2.19→38.865 Å / SU ML: 0.42 / Cross valid method: FREE R-VALUE / σ(F): 1.19 / Phase error: 33.01
RfactorNum. reflection% reflectionSelection details
Rfree0.2757 9141 4.99 %ramdom
Rwork0.212 ---
obs0.2151 93206 93.97 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.19→38.865 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12846 0 529 386 13761
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913850
X-RAY DIFFRACTIONf_angle_d1.20818971
X-RAY DIFFRACTIONf_dihedral_angle_d16.6135038
X-RAY DIFFRACTIONf_chiral_restr0.0761956
X-RAY DIFFRACTIONf_plane_restr0.0052422
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1901-2.2150.44321640.43553049X-RAY DIFFRACTION50
2.215-2.2410.41792920.36915488X-RAY DIFFRACTION89
2.241-2.26840.4042610.36265497X-RAY DIFFRACTION88
2.2684-2.29710.35333130.33915795X-RAY DIFFRACTION93
2.2971-2.32730.38493370.34815741X-RAY DIFFRACTION95
2.3273-2.35920.37012760.34185914X-RAY DIFFRACTION94
2.3592-2.39290.38663140.32875737X-RAY DIFFRACTION94
2.3929-2.42860.37293040.3165814X-RAY DIFFRACTION94
2.4286-2.46650.35213100.31445614X-RAY DIFFRACTION91
2.4665-2.5070.37413000.30965396X-RAY DIFFRACTION88
2.507-2.55020.35012780.29636047X-RAY DIFFRACTION98
2.5502-2.59650.34743430.2785959X-RAY DIFFRACTION97
2.5965-2.64650.34223510.27386033X-RAY DIFFRACTION98
2.6465-2.70050.32953400.27545942X-RAY DIFFRACTION96
2.7005-2.75920.34583300.2466018X-RAY DIFFRACTION98
2.7592-2.82340.30252750.24325989X-RAY DIFFRACTION96
2.8234-2.89390.29273520.22385911X-RAY DIFFRACTION98
2.8939-2.97220.31283050.22746101X-RAY DIFFRACTION97
2.9722-3.05960.29282640.2116002X-RAY DIFFRACTION98
3.0596-3.15830.28952810.21645973X-RAY DIFFRACTION95
3.1583-3.27110.28623120.20555673X-RAY DIFFRACTION92
3.2711-3.4020.28173370.20086057X-RAY DIFFRACTION99
3.402-3.55670.27333300.1926035X-RAY DIFFRACTION98
3.5567-3.74410.2523360.17966060X-RAY DIFFRACTION98
3.7441-3.97850.20043010.17036109X-RAY DIFFRACTION98
3.9785-4.28530.25593160.1695991X-RAY DIFFRACTION97
4.2853-4.71590.21533060.1485914X-RAY DIFFRACTION96
4.7159-5.39670.22073150.15595988X-RAY DIFFRACTION96
5.3967-6.79340.27123190.17876037X-RAY DIFFRACTION98
6.7934-38.87070.20842790.20266013X-RAY DIFFRACTION97
Refinement TLS params.Method: refined / Origin x: 82.8925 Å / Origin y: -0.9256 Å / Origin z: -189.2348 Å
111213212223313233
T0.2927 Å2-0.0478 Å2-0.0609 Å2-0.2458 Å20.048 Å2--0.2673 Å2
L0.3033 °2-0.0526 °2-0.3126 °2-0.2586 °20.0578 °2--1.0209 °2
S0.0531 Å °0.0106 Å °0.0028 Å °-0.0117 Å °0.025 Å °0.0484 Å °-0.0026 Å °-0.0967 Å °-0.0619 Å °
Refinement TLS groupSelection details: all

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