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- PDB-9q4y: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 9q4y
TitleStructure of human endothelial nitric oxide synthase heme domain bound with 6-((2,3-difluoro-5-(2-(methylamino)ethyl)phenoxy)methyl)-4-methylpyridin-2-amine
ComponentsNitric oxide synthase 3
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / nitric oxide synthase inhibitor binding / OXIDOREDUCTASE-INHIBITOR complex / OXIDOREDUCTASE / 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 / flavin adenine dinucleotide binding / NADP 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
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 ...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
Similarity search - Domain/homology
: / 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 / FOURIER SYNTHESIS / Resolution: 2.1 Å
AuthorsLi, H. / Poulos, T.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM131920 United States
CitationJournal: To Be Published
Title: Highly potent, selective, and membrane permeable ether linked 2-aminopyridine-based human neuronal nitric oxide synthase inhibitors
Authors: Ansari, A. / Chrzanowski, R.T. / Li, H. / Hardy, C.D. / Poulos, T.L. / Silverman, R.B.
History
DepositionAug 20, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 10, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nitric oxide synthase 3
B: Nitric oxide synthase 3
C: Nitric oxide synthase 3
D: Nitric oxide synthase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)205,06942
Polymers197,3834
Non-polymers7,68638
Water2,918162
1
A: Nitric oxide synthase 3
B: Nitric oxide synthase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,50921
Polymers98,6922
Non-polymers3,81719
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10930 Å2
ΔGint-151 kcal/mol
Surface area34110 Å2
MethodPISA
2
C: Nitric oxide synthase 3
D: Nitric oxide synthase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,56121
Polymers98,6922
Non-polymers3,86919
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10870 Å2
ΔGint-145 kcal/mol
Surface area33710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.644, 152.953, 108.818
Angle α, β, γ (deg.)90.00, 90.55, 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 3 / Constitutive NOS / cNOS / EC-NOS / NOS type III / NOSIII / Nitric oxide synthase / endothelial / ...Constitutive NOS / cNOS / EC-NOS / NOS type III / NOSIII / Nitric oxide synthase / endothelial / Endothelial NOS / eNOS


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 , 10 types, 200 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-A1CN3 / 6-({2,3-difluoro-5-[2-(methylamino)ethyl]phenoxy}methyl)-4-methylpyridin-2-amine


Mass: 307.338 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C16H19F2N3O / Feature type: SUBJECT OF INVESTIGATION
#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.: 8 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 7 / 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-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#9: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#10: Chemical ChemComp-GD / GADOLINIUM ATOM


Mass: 157.250 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Gd
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 162 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: SSRL / Beamline: BL12-2 / Wavelength: 0.886 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 21, 2024 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.886 Å / Relative weight: 1
ReflectionResolution: 2.1→39.05 Å / Num. obs: 112399 / % possible obs: 99.1 % / Redundancy: 4.8 % / CC1/2: 0.996 / Rmerge(I) obs: 0.139 / Rpim(I) all: 0.068 / Rrim(I) all: 0.156 / Χ2: 0.95 / Net I/σ(I): 5.6 / Num. measured all: 542340
Reflection shellResolution: 2.1→2.14 Å / Redundancy: 4.8 % / Rmerge(I) obs: 3.282 / Num. unique obs: 5674 / CC1/2: 0.326 / Rpim(I) all: 1.662 / Rrim(I) all: 3.689 / Χ2: 0.84 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.1→39.049 Å / SU ML: 0.42 / Cross valid method: FREE R-VALUE / σ(F): 0.9 / Phase error: 41.75 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2933 10545 4.99 %random
Rwork0.2361 ---
obs0.2389 106964 94.15 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→39.049 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12834 0 493 162 13489
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01113763
X-RAY DIFFRACTIONf_angle_d1.04218754
X-RAY DIFFRACTIONf_dihedral_angle_d16.0758023
X-RAY DIFFRACTIONf_chiral_restr0.0541940
X-RAY DIFFRACTIONf_plane_restr0.0062409
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1001-2.1240.64381800.57032971X-RAY DIFFRACTION42
2.124-2.1490.53722550.53644912X-RAY DIFFRACTION70
2.149-2.17520.53983000.50835716X-RAY DIFFRACTION80
2.1752-2.20270.52633110.49966244X-RAY DIFFRACTION88
2.2027-2.23170.50783730.47626540X-RAY DIFFRACTION92
2.2317-2.26220.44523350.46616677X-RAY DIFFRACTION94
2.2622-2.29460.47313390.4526921X-RAY DIFFRACTION96
2.2946-2.32880.46643810.43056865X-RAY DIFFRACTION98
2.3288-2.36520.44423710.42716983X-RAY DIFFRACTION98
2.3652-2.4040.45143690.42047001X-RAY DIFFRACTION98
2.404-2.44540.47633730.39336962X-RAY DIFFRACTION99
2.4454-2.48990.44344000.38537080X-RAY DIFFRACTION99
2.4899-2.53770.43183550.36116979X-RAY DIFFRACTION99
2.5377-2.58950.39643550.35647089X-RAY DIFFRACTION99
2.5895-2.64580.39524080.34386895X-RAY DIFFRACTION98
2.6458-2.70740.36494100.32236993X-RAY DIFFRACTION98
2.7074-2.77510.32263710.28086895X-RAY DIFFRACTION98
2.7751-2.85010.30883320.27456798X-RAY DIFFRACTION95
2.8501-2.93390.3463760.27126600X-RAY DIFFRACTION94
2.9339-3.02860.33813160.25247149X-RAY DIFFRACTION99
3.0286-3.13680.33753530.25177136X-RAY DIFFRACTION100
3.1368-3.26230.32513490.23857048X-RAY DIFFRACTION100
3.2623-3.41070.30213880.22687077X-RAY DIFFRACTION100
3.4107-3.59040.26743890.20167044X-RAY DIFFRACTION100
3.5904-3.81520.27613720.18777070X-RAY DIFFRACTION100
3.8152-4.10940.20693890.17287074X-RAY DIFFRACTION99
4.1094-4.52240.23643610.15477059X-RAY DIFFRACTION99
4.5224-5.17560.19793540.13866991X-RAY DIFFRACTION98
5.1756-6.51570.22163430.15816945X-RAY DIFFRACTION97
6.5157-39.0490.20423370.18077091X-RAY DIFFRACTION99
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)
10.5143-0.20070.17731.7386-0.02631.21240.15350.1993-0.1932-0.0215-0.0842-0.09680.74330.1475-0.04070.99780.03-0.11230.4675-0.05960.4551-30.7618-36.7682-76.7148
20.7275-0.2790.42710.6688-0.2322.5336-0.0829-0.00390.00180.25880.1122-0.0334-0.0882-0.0656-0.01160.67-0.0259-0.0730.33560.0110.412-40.8654-13.2711-49.292
30.61030.1689-0.26072.02110.21551.37860.1915-0.27670.239-0.11020.0023-0.1694-0.60060.3785-0.12890.7155-0.12940.10820.5945-0.150.4828-1.738928.7652-86.481
40.87940.5361-0.04171.55120.3042.1641-0.08170.00720.0134-0.64160.12630.0394-0.27790.0199-0.04040.31280.06570.01650.3238-0.01290.373-11.68995.5566-114.2188
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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