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- PDB-9cw4: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 9cw4
TitleStructure of human endothelial nitric oxide synthase heme domain bound with 6-(3-fluoro-5-((methylamino)methyl)phenyl)-4-methylpyridin-2-amine dihydrochloride
ComponentsNitric oxide synthase, endothelial
KeywordsOXIDOREDUCTASE/INHIBITOR / nitric oxide synthase inhibitor binding / 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 ION / 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 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: Bioorg.Med.Chem. / Year: 2025
Title: Truncated pyridinylbenzylamines: Potent, selective, and highly membrane permeable inhibitors of human neuronal nitric oxide synthase.
Authors: Vasu, D. / Do, H.T. / Li, H. / Hardy, C.D. / Poulos, T.L. / Silverman, R.B.
History
DepositionJul 29, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 30, 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, 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)205,34242
Polymers197,3834
Non-polymers7,95938
Water6,305350
1
A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,88022
Polymers98,6922
Non-polymers4,18920
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11420 Å2
ΔGint-156 kcal/mol
Surface area34010 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,46220
Polymers98,6922
Non-polymers3,77018
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11270 Å2
ΔGint-158 kcal/mol
Surface area33800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.201, 152.998, 108.814
Angle α, β, γ (deg.)90.00, 90.49, 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, 388 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-A1A0H / (6M)-6-{3-fluoro-5-[(methylamino)methyl]phenyl}-4-methylpyridin-2-amine


Mass: 245.295 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H16FN3 / 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.: 10 / 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.: 6 / 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-GD3 / GADOLINIUM ION


Mass: 157.250 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Gd
#9: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 350 / 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: 278 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 10-12% PEG3350, 0.1M Bis-Tris, 0.2-0.3M Magnesium 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: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 23, 2022 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2→38.91 Å / Num. obs: 121391 / % possible obs: 93.3 % / Redundancy: 4.9 % / CC1/2: 0.988 / Rmerge(I) obs: 0.203 / Rpim(I) all: 0.098 / Rrim(I) all: 0.226 / Χ2: 0.78 / Net I/σ(I): 4 / Num. measured all: 592403
Reflection shellResolution: 2→2.03 Å / % possible obs: 90.7 % / Redundancy: 4.6 % / Rmerge(I) obs: 5.079 / Num. measured all: 27180 / Num. unique obs: 5847 / CC1/2: 0.403 / Rpim(I) all: 2.526 / Rrim(I) all: 5.693 / Χ2: 0.55 / Net I/σ(I) obs: 0.3

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
Aimlessdata scaling
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→38.908 Å / SU ML: 0.35 / Cross valid method: FREE R-VALUE / σ(F): 0.97 / Phase error: 34.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2836 11105 5.04 %random
Rwork0.2232 ---
obs0.2262 111993 85.38 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2→38.908 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12833 0 498 350 13681
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0113786
X-RAY DIFFRACTIONf_angle_d1.08518776
X-RAY DIFFRACTIONf_dihedral_angle_d15.1728029
X-RAY DIFFRACTIONf_chiral_restr0.0561945
X-RAY DIFFRACTIONf_plane_restr0.0062410
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0002-2.0230.625140.5021287X-RAY DIFFRACTION3
2.023-2.04680.4903790.46561387X-RAY DIFFRACTION17
2.0468-2.07170.46383740.40075655X-RAY DIFFRACTION71
2.0717-2.09790.39643460.37276369X-RAY DIFFRACTION78
2.0979-2.12550.39033920.36247083X-RAY DIFFRACTION87
2.1255-2.15470.39873940.357292X-RAY DIFFRACTION90
2.1547-2.18540.4013720.34627590X-RAY DIFFRACTION91
2.1854-2.21810.36044160.33617537X-RAY DIFFRACTION93
2.2181-2.25270.39653880.33617563X-RAY DIFFRACTION92
2.2527-2.28960.34313830.3157718X-RAY DIFFRACTION94
2.2896-2.32910.34754190.29617598X-RAY DIFFRACTION93
2.3291-2.37150.35533930.29487643X-RAY DIFFRACTION93
2.3715-2.41710.33374060.29447395X-RAY DIFFRACTION91
2.4171-2.46640.38774120.29997181X-RAY DIFFRACTION88
2.4664-2.520.32663510.27256770X-RAY DIFFRACTION83
2.52-2.57860.31774030.24097897X-RAY DIFFRACTION96
2.5786-2.64310.2794430.23427770X-RAY DIFFRACTION96
2.6431-2.71460.30544350.23787704X-RAY DIFFRACTION95
2.7146-2.79440.31014000.22567752X-RAY DIFFRACTION95
2.7944-2.88460.29684210.24127699X-RAY DIFFRACTION94
2.8846-2.98760.29413840.24227638X-RAY DIFFRACTION93
2.9876-3.10720.31973570.23037536X-RAY DIFFRACTION91
3.1072-3.24860.34143500.23416819X-RAY DIFFRACTION84
3.2486-3.41970.28534220.21347680X-RAY DIFFRACTION94
3.4197-3.63380.25954320.19577888X-RAY DIFFRACTION96
3.6338-3.91420.23753790.18017770X-RAY DIFFRACTION95
3.9142-4.30760.24994200.17297535X-RAY DIFFRACTION93
4.3076-4.92990.22623450.1647103X-RAY DIFFRACTION86
4.9299-6.20710.23214220.17697749X-RAY DIFFRACTION96
6.2071-38.9080.22553530.20237489X-RAY DIFFRACTION91
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)
10.91750.3096-0.18911.8104-0.45941.62850.16520.27810.3390.11790.14660.2374-0.616-0.44-0.15440.52130.15780.13880.46220.17390.396162.838631.9638-185.5314
21.1645-0.493-0.12281.6129-1.0212.0145-0.0356-0.08360.02690.47030.1024-0.0031-0.2717-0.0802-0.03970.3787-0.0428-0.01550.21810.00360.251372.84288.4495-157.7465
30.7644-0.02160.3021.6429-0.13081.54790.1045-0.2346-0.256-0.07630.03720.13770.5555-0.2568-0.06790.6026-0.0382-0.08640.35730.0970.355791.4429-34.269-195.3361
41.02140.37620.20290.8206-0.18972.2224-0.09620.09590.0077-0.25660.09660.0478-0.04970.052-0.01740.44030.038-0.03320.2016-0.00010.2456101.4315-10.486-222.7205
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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