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

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Basic information

Entry
Database: PDB / ID: 9cwj
TitleStructure of human endothelial nitric oxide synthase heme domain bound with 6-(5-((4,4-difluoropiperidin-1-yl)methyl)-2,3-difluorophenyl)-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 / cell redox homeostasis / lung development / 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 / cytosol / cytoplasm
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: 1.9 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)206,14246
Polymers197,3834
Non-polymers8,75942
Water13,385743
1
A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,53026
Polymers98,6922
Non-polymers4,83824
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11950 Å2
ΔGint-157 kcal/mol
Surface area32700 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,61320
Polymers98,6922
Non-polymers3,92118
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11510 Å2
ΔGint-157 kcal/mol
Surface area32580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.942, 151.786, 107.919
Angle α, β, γ (deg.)90.00, 90.78, 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, 785 molecules

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


Mass: 616.487 Da / Num. of mol.: 4 / Source method: isolated from a natural source / 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-A1A0A / (6M)-6-{5-[(4,4-difluoropiperidin-1-yl)methyl]-2,3-difluorophenyl}-4-methylpyridin-2-amine


Mass: 353.357 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H19F4N3 / 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.: 10 / 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.: 743 / 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: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Sep 18, 2022 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.9→49.21 Å / Num. obs: 147478 / % possible obs: 99.1 % / Redundancy: 4.6 % / CC1/2: 0.996 / Rmerge(I) obs: 0.14 / Rpim(I) all: 0.069 / Rrim(I) all: 0.156 / Net I/σ(I): 6 / Num. measured all: 677732
Reflection shellResolution: 1.9→1.93 Å / % possible obs: 98 % / Redundancy: 4.2 % / Rmerge(I) obs: 1.985 / Num. measured all: 30236 / Num. unique obs: 7174 / CC1/2: 0.456 / Rpim(I) all: 0.996 / Rrim(I) all: 2.231 / Net I/σ(I) obs: 0.6

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Processing

Software
NameVersionClassification
PHENIX1.11.1_2575refinement
Aimlessdata scaling
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.9→49.21 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 30.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2375 14685 5.04 %random
Rwork0.1961 ---
obs0.1982 147134 98.91 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.9→49.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12824 0 550 743 14117
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913820
X-RAY DIFFRACTIONf_angle_d0.96818831
X-RAY DIFFRACTIONf_dihedral_angle_d14.8688050
X-RAY DIFFRACTIONf_chiral_restr0.0521952
X-RAY DIFFRACTIONf_plane_restr0.0062409
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.92160.37174540.33159043X-RAY DIFFRACTION97
1.9216-1.94420.33694850.31739190X-RAY DIFFRACTION99
1.9442-1.96790.34884550.30869323X-RAY DIFFRACTION99
1.9679-1.99280.36665120.2969069X-RAY DIFFRACTION99
1.9928-2.0190.3214900.29759196X-RAY DIFFRACTION99
2.019-2.04670.33995350.28429219X-RAY DIFFRACTION98
2.0467-2.07590.3375340.29529062X-RAY DIFFRACTION99
2.0759-2.10690.33625320.28559205X-RAY DIFFRACTION98
2.1069-2.13980.30985140.26529127X-RAY DIFFRACTION99
2.1398-2.17490.3284540.27459321X-RAY DIFFRACTION99
2.1749-2.21240.29295030.24719183X-RAY DIFFRACTION99
2.2124-2.25270.30834450.24539319X-RAY DIFFRACTION99
2.2527-2.2960.2714970.23089224X-RAY DIFFRACTION99
2.296-2.34290.27435050.23049264X-RAY DIFFRACTION99
2.3429-2.39380.2894760.22939219X-RAY DIFFRACTION99
2.3938-2.44950.27215210.22479276X-RAY DIFFRACTION99
2.4495-2.51070.28164690.22249177X-RAY DIFFRACTION99
2.5107-2.57860.24734930.20379219X-RAY DIFFRACTION98
2.5786-2.65450.23795460.19549118X-RAY DIFFRACTION99
2.6545-2.74020.24075060.18959329X-RAY DIFFRACTION100
2.7402-2.83810.2344600.19739287X-RAY DIFFRACTION99
2.8381-2.95170.24164960.19689325X-RAY DIFFRACTION99
2.9517-3.0860.23554310.18879294X-RAY DIFFRACTION99
3.086-3.24870.24614700.18549238X-RAY DIFFRACTION99
3.2487-3.45220.21065020.17329162X-RAY DIFFRACTION99
3.4522-3.71860.20665140.16459329X-RAY DIFFRACTION100
3.7186-4.09270.18174970.15069261X-RAY DIFFRACTION100
4.0927-4.68450.17314520.13549330X-RAY DIFFRACTION99
4.6845-5.90040.19455110.15149227X-RAY DIFFRACTION99
5.9004-49.210.20734260.19589309X-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)
10.78380.3855-0.39771.4724-0.46391.57130.2330.40420.26960.0270.17350.2283-0.5435-0.5357-0.10750.42550.1830.15140.47890.21380.387363.572831.7086-184.014
20.8672-0.1963-0.2731.1157-0.69282.04520.07-0.03510.01750.26870.04810.0045-0.1417-0.0975-0.08180.2381-0.0617-0.00610.22280.0140.277373.3378.3772-156.4296
30.69440.00490.46721.5352-0.25331.5190.1684-0.2641-0.21790.07990.03320.10340.5429-0.2513-0.06280.4473-0.0375-0.06030.30650.1040.326592.0221-33.9918-193.7188
40.80930.26240.41710.6177-0.04832.274-0.03470.0393-0.0261-0.09570.06950.0002-0.08270.1531-0.02260.17990.0435-0.00680.151-0.00710.2159102.1228-10.2973-220.8645
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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