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- PDB-9q4z: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 9q4z
TitleStructure of human endothelial nitric oxide synthase heme domain bound with 6-((5-(2-(ethyl(methyl)amino)ethyl)-2,3-difluorophenxy)methyl)-4-methylphridin-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 / 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
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: 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: 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)205,54844
Polymers197,3834
Non-polymers8,16540
Water15,637868
1
A: Nitric oxide synthase 3
B: Nitric oxide synthase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,81423
Polymers98,6922
Non-polymers4,12321
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11750 Å2
ΔGint-162 kcal/mol
Surface area33320 Å2
MethodPISA
2
C: Nitric oxide synthase 3
D: Nitric oxide synthase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,73421
Polymers98,6922
Non-polymers4,04219
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11160 Å2
ΔGint-153 kcal/mol
Surface area32820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.077, 152.807, 108.353
Angle α, β, γ (deg.)90.00, 90.75, 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, 908 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-A1CN4 / 6-[(5-{2-[ethyl(methyl)amino]ethyl}-2,3-difluorophenoxy)methyl]-4-methylpyridin-2-amine


Mass: 335.392 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H23F2N3O / 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.: 8 / 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-GD / GADOLINIUM ATOM


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: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#11: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 868 / 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: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 3, 2024 / 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→47.223 Å / Num. obs: 153263 / % possible obs: 100 % / Redundancy: 9.5 % / CC1/2: 0.992 / Rmerge(I) obs: 0.247 / Rpim(I) all: 0.085 / Rrim(I) all: 0.262 / Net I/σ(I): 5.4
Reflection shellResolution: 1.9→1.93 Å / Redundancy: 9.5 % / Rmerge(I) obs: 3.271 / Num. unique obs: 7646 / CC1/2: 0.39 / Rpim(I) all: 1.12 / Rrim(I) all: 3.461 / % possible all: 100

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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: 1.9→47.223 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 0.03 / Phase error: 31.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2657 13789 5.03 %random
Rwork0.2138 ---
obs0.2164 138494 90.25 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.9→47.223 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12844 0 508 868 14220
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913785
X-RAY DIFFRACTIONf_angle_d1.00518770
X-RAY DIFFRACTIONf_dihedral_angle_d15.5948021
X-RAY DIFFRACTIONf_chiral_restr0.0521941
X-RAY DIFFRACTIONf_plane_restr0.0062410
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.9-1.92160.41992440.33334912X-RAY DIFFRACTION51
1.9216-1.94420.39512420.3285447X-RAY DIFFRACTION56
1.9442-1.96790.36463320.3025677X-RAY DIFFRACTION60
1.9679-1.99280.37753210.31346352X-RAY DIFFRACTION65
1.9928-2.01910.34073760.31516644X-RAY DIFFRACTION69
2.0191-2.04670.36173690.2997063X-RAY DIFFRACTION74
2.0467-2.0760.34724640.29697534X-RAY DIFFRACTION78
2.076-2.10690.35144450.28937804X-RAY DIFFRACTION82
2.1069-2.13990.30724750.28178428X-RAY DIFFRACTION87
2.1399-2.17490.34934690.28288734X-RAY DIFFRACTION91
2.1749-2.21250.30894660.27079271X-RAY DIFFRACTION96
2.2125-2.25270.36835280.27639507X-RAY DIFFRACTION100
2.2527-2.2960.30944460.26059695X-RAY DIFFRACTION100
2.296-2.34290.2885620.25769543X-RAY DIFFRACTION100
2.3429-2.39380.3274760.25279688X-RAY DIFFRACTION100
2.3938-2.44950.3285260.24619530X-RAY DIFFRACTION100
2.4495-2.51080.28615470.23949633X-RAY DIFFRACTION100
2.5108-2.57860.27424600.23399599X-RAY DIFFRACTION100
2.5786-2.65450.28345650.23279557X-RAY DIFFRACTION100
2.6545-2.74020.29245330.22899618X-RAY DIFFRACTION100
2.7402-2.83810.28154710.22539650X-RAY DIFFRACTION100
2.8381-2.95170.27775440.23529489X-RAY DIFFRACTION100
2.9517-3.0860.29494380.22939720X-RAY DIFFRACTION100
3.086-3.24870.2754880.21089580X-RAY DIFFRACTION100
3.2487-3.45220.24695260.20439639X-RAY DIFFRACTION100
3.4522-3.71860.26035260.18759605X-RAY DIFFRACTION100
3.7186-4.09270.20084950.16659575X-RAY DIFFRACTION100
4.0927-4.68440.19874870.15059655X-RAY DIFFRACTION100
4.6844-5.90010.21825310.15539588X-RAY DIFFRACTION100
5.9001-47.2230.20044370.1889621X-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)
10.4893-0.08370.10430.98450.07380.9980.10480.3699-0.0773-0.1393-0.0313-0.08710.60160.1123-0.00130.53830.009-0.04360.1096-0.130.1554-30.3805-38.7901-76.3142
20.6959-0.14890.10620.53950.07781.49440.0047-0.0464-0.0030.0260.06960.00850.03-0.0907-0.06620.1419-0.0153-0.00150.11490.0110.1668-40.7452-15.2643-49.2204
30.5689-0.1022-0.03971.04180.19170.99380.0798-0.26570.18710.01080.0817-0.1884-0.32150.2496-0.07720.3349-0.08630.06390.2942-0.12510.2421-1.151626.624-86.1281
40.84330.2784-0.05040.78650.48431.4510.01920.0353-0.0341-0.12120.1062-0.048-0.10620.0594-0.0970.14740.02420.00260.1266-0.01370.1656-11.31393.4633-113.7799
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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