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

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Basic information

Entry
Database: PDB / ID: 9mwn
TitleStructure of human endothelial nitric oxide synthase heme domain bound with N-(4-(2-((3-(thiophene-2-carboximidamido)benzyl)amino)ethyl)phenyl)thiophene-2-carboximidamide
ComponentsNitric oxide synthase 3
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor binding
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 / aortic valve morphogenesis / arginine binding / 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 / blood vessel remodeling / nitric-oxide synthase (NADPH) / 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 / negative regulation of blood pressure / regulation of sodium ion transport / 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 / angiogenesis / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / 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
ACETATE ION / GADOLINIUM ATOM / Chem-H44 / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / 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: To be published
Title: A step forward for neuronal Nitric Oxide Synthase Inhibitors against Melanoma
Authors: Awasthi, A. / Li, H. / Hardy, C.D. / Poulos, T.L. / Silverman, R.B.
History
DepositionJan 17, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 26, 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)206,10040
Polymers197,9004
Non-polymers8,20036
Water15,097838
1
A: Nitric oxide synthase 3
B: Nitric oxide synthase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,08320
Polymers98,9502
Non-polymers4,13318
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11130 Å2
ΔGint-150 kcal/mol
Surface area32660 Å2
MethodPISA
2
C: Nitric oxide synthase 3
D: Nitric oxide synthase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,01720
Polymers98,9502
Non-polymers4,06818
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11470 Å2
ΔGint-155 kcal/mol
Surface area32830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.639, 151.731, 108.312
Angle α, β, γ (deg.)90.00, 90.88, 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: 49474.949 Da / Num. of mol.: 4 / Fragment: heme domain
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, 874 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-H44 / N-(4-{2-[(3-{[(E)-imino(thiophen-2-yl)methyl]amino}benzyl)amino]ethyl}phenyl)thiophene-2-carboximidamide


Mass: 459.630 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H25N5S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H3O2
#6: 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
#7: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#8: Chemical
ChemComp-CL / CHLORIDE ION


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


Mass: 157.250 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Gd
#10: Chemical ChemComp-ZN / ZINC ION


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


Mass: 18.015 Da / Num. of mol.: 838 / 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: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418 Å
DetectorType: RIGAKU HyPix-6000HE / Detector: PIXEL / Date: Apr 26, 2023 / Details: VariMax Optic
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→29.38 Å / Num. obs: 129489 / % possible obs: 99.9 % / Redundancy: 10.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.155 / Rpim(I) all: 0.051 / Rrim(I) all: 0.163 / Net I/σ(I): 10.3 / Num. measured all: 1319233
Reflection shellResolution: 2→2.03 Å / % possible obs: 99.6 % / Redundancy: 7.5 % / Rmerge(I) obs: 1.111 / Num. measured all: 47890 / Num. unique obs: 6356 / CC1/2: 0.581 / Rpim(I) all: 0.434 / Rrim(I) all: 1.194 / Net I/σ(I) obs: 1.6

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
Aimlessdata scaling
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→29.38 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 25.02 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2345 12941 5.06 %random
Rwork0.1916 ---
obs0.1937 129311 99.82 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2→29.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12821 0 523 838 14182
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00813786
X-RAY DIFFRACTIONf_angle_d1.09618786
X-RAY DIFFRACTIONf_dihedral_angle_d15.7128017
X-RAY DIFFRACTIONf_chiral_restr0.0531939
X-RAY DIFFRACTIONf_plane_restr0.0062421
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2-2.02270.34044370.31677992X-RAY DIFFRACTION99
2.0227-2.04650.30814390.30018130X-RAY DIFFRACTION100
2.0465-2.07150.32495030.29567945X-RAY DIFFRACTION100
2.0715-2.09770.33344590.29118103X-RAY DIFFRACTION100
2.0977-2.12530.30554590.28318115X-RAY DIFFRACTION100
2.1253-2.15440.33054160.26997999X-RAY DIFFRACTION100
2.1544-2.18520.32034120.26828144X-RAY DIFFRACTION100
2.1852-2.21780.32184380.26598177X-RAY DIFFRACTION100
2.2178-2.25240.29524390.2528042X-RAY DIFFRACTION100
2.2524-2.28930.27893700.24638194X-RAY DIFFRACTION100
2.2893-2.32880.28344800.23318028X-RAY DIFFRACTION100
2.3288-2.37110.28844000.2328132X-RAY DIFFRACTION100
2.3711-2.41670.28664450.22358117X-RAY DIFFRACTION100
2.4167-2.4660.27154450.2248083X-RAY DIFFRACTION100
2.466-2.51960.26834380.20368095X-RAY DIFFRACTION100
2.5196-2.57820.24724140.2048229X-RAY DIFFRACTION100
2.5782-2.64260.23054710.19757953X-RAY DIFFRACTION100
2.6426-2.7140.24714650.20188178X-RAY DIFFRACTION100
2.714-2.79380.23684020.20018044X-RAY DIFFRACTION100
2.7938-2.88390.25354530.1998065X-RAY DIFFRACTION100
2.8839-2.98690.23953940.19378167X-RAY DIFFRACTION100
2.9869-3.10630.23443780.18528179X-RAY DIFFRACTION100
3.1063-3.24750.24294240.18588092X-RAY DIFFRACTION100
3.2475-3.41850.20974460.17928074X-RAY DIFFRACTION100
3.4185-3.63230.19464340.1638139X-RAY DIFFRACTION100
3.6323-3.91220.20513960.15068140X-RAY DIFFRACTION100
3.9122-4.30480.17684590.14038110X-RAY DIFFRACTION100
4.3048-4.92520.17043930.1318163X-RAY DIFFRACTION100
4.9252-6.19570.2134450.15028085X-RAY DIFFRACTION100
6.1957-29.380.18543870.17778147X-RAY DIFFRACTION100
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)
10.7965-0.06630.46241.8290.09461.80270.14720.3045-0.2754-0.16610.046-0.17580.52940.2612-0.0940.36450.0367-0.04630.2333-0.12540.28-29.613-38.709-76.379
20.8098-0.22360.22610.87610.08792.5556-0.0153-0.0333-0.03690.06290.06540.0472-0.0693-0.1507-0.04420.1257-0.03030.00240.0995-0.00110.1752-39.907-15.267-49.131
30.7935-0.3309-0.65421.68330.5331.90930.2236-0.5510.3193-0.10450.3347-0.4064-0.70490.6861-0.12970.4526-0.23620.16030.474-0.3290.3747-0.79226.663-86.036
40.98150.0909-0.4011.35340.71922.4920.07470.03530.0172-0.23420.0621-0.0393-0.13240.0992-0.10990.13010.0428-0.00950.1249-0.01990.1739-10.7333.588-113.739
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 68:480 )A68 - 480
2X-RAY DIFFRACTION2( CHAIN B AND RESID 67:480 )B67 - 480
3X-RAY DIFFRACTION3( CHAIN C AND RESID 68:480 )C68 - 480
4X-RAY DIFFRACTION4( CHAIN D AND RESID 67:480 )D67 - 480

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