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- PDB-9mz4: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 9mz4
TitleStructure of human endothelial nitric oxide synthase heme domain bound 7-(3-(aminomethyl)-4-(cyclopropylmethoxy)phenyl)-6-fluoro-4-methylquinolin-2-amine
ComponentsNitric oxide synthase 3
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor binding / 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 / positive regulation of blood vessel endothelial cell migration / nitric oxide mediated signal transduction / blood vessel remodeling / nitric-oxide synthase (NADPH) / 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
: / 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: 1.94 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: Design and synthesis of 7-aryl-6-fluoro-2-aminoquinolines as potent and highly selective human neuronal nitric oxide synthase inhibitors
Authors: Ansari, A. / Rathnayake, A.D. / Li, H. / Hardy, C.D. / Poulos, T.L. / Silverman, R.B.
History
DepositionJan 22, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 3, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)205,70445
Polymers197,3834
Non-polymers8,32141
Water9,656536
1
A: Nitric oxide synthase 3
B: Nitric oxide synthase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,84623
Polymers98,6922
Non-polymers4,15521
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area13320 Å2
ΔGint-163 kcal/mol
Surface area32390 Å2
MethodPISA
2
C: Nitric oxide synthase 3
D: Nitric oxide synthase 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,85822
Polymers98,6922
Non-polymers4,16720
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area12860 Å2
ΔGint-158 kcal/mol
Surface area31940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.811, 151.138, 107.785
Angle α, β, γ (deg.)90.00, 90.61, 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, 577 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-A1BU3 / (7P)-7-[3-(aminomethyl)-4-(cyclopropylmethoxy)phenyl]-6-fluoro-4-methylquinolin-2-amine


Mass: 351.417 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H22FN3O / 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.: 9 / 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.: 536 / 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: 2.43 Å3/Da / Density % sol: 49.32 % / 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: 8.2.1 / Wavelength: 0.97947 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 8, 2024 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97947 Å / Relative weight: 1
ReflectionResolution: 1.94→49.05 Å / Num. obs: 136728 / % possible obs: 98.6 % / Redundancy: 5 % / CC1/2: 0.994 / Rmerge(I) obs: 0.157 / Rpim(I) all: 0.075 / Rrim(I) all: 0.175 / Net I/σ(I): 4 / Num. measured all: 682371
Reflection shellResolution: 1.94→1.97 Å / Redundancy: 5 % / Rmerge(I) obs: 3.462 / Num. unique obs: 6757 / CC1/2: 0.24 / Rpim(I) all: 1.654 / Rrim(I) all: 3.847 / % possible all: 98.4

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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: 1.94→46.411 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 0.02 / Phase error: 29.72 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2536 13710 5.06 %random
Rwork0.2039 ---
obs0.2064 136615 98.55 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.94→46.411 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12851 0 522 536 13909
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00813825
X-RAY DIFFRACTIONf_angle_d1.01718841
X-RAY DIFFRACTIONf_dihedral_angle_d15.4698048
X-RAY DIFFRACTIONf_chiral_restr0.0531948
X-RAY DIFFRACTIONf_plane_restr0.0062414
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.94-1.9620.33934580.31238627X-RAY DIFFRACTION98
1.962-1.98510.39644390.30368510X-RAY DIFFRACTION99
1.9851-2.00930.34684660.30568605X-RAY DIFFRACTION98
2.0093-2.03480.31644850.28748500X-RAY DIFFRACTION99
2.0348-2.06150.35055270.30668414X-RAY DIFFRACTION98
2.0615-2.08980.3614680.2928633X-RAY DIFFRACTION99
2.0898-2.11960.30514850.27548535X-RAY DIFFRACTION99
2.1196-2.15130.33164580.27258546X-RAY DIFFRACTION99
2.1513-2.18490.30454270.27178691X-RAY DIFFRACTION99
2.1849-2.22070.35024810.28758501X-RAY DIFFRACTION99
2.2207-2.2590.31294110.29018779X-RAY DIFFRACTION99
2.259-2.30010.33094820.25668452X-RAY DIFFRACTION99
2.3001-2.34430.28564410.24528676X-RAY DIFFRACTION99
2.3443-2.39220.31844590.2428578X-RAY DIFFRACTION99
2.3922-2.44420.30314820.23768563X-RAY DIFFRACTION99
2.4442-2.5010.28634600.23418502X-RAY DIFFRACTION98
2.501-2.56360.31254210.23898113X-RAY DIFFRACTION92
2.5636-2.63290.28384990.22618295X-RAY DIFFRACTION97
2.6329-2.71030.2534730.228659X-RAY DIFFRACTION100
2.7103-2.79780.28234410.21818745X-RAY DIFFRACTION100
2.7978-2.89780.24794840.21398625X-RAY DIFFRACTION100
2.8978-3.01380.26713980.19838649X-RAY DIFFRACTION100
3.0138-3.15090.30634190.21738747X-RAY DIFFRACTION100
3.1509-3.3170.26214620.19738638X-RAY DIFFRACTION99
3.317-3.52480.23534850.18388616X-RAY DIFFRACTION100
3.5248-3.79680.22624400.17548658X-RAY DIFFRACTION99
3.7968-4.17870.20214760.16298683X-RAY DIFFRACTION99
4.1787-4.78280.19794230.15318508X-RAY DIFFRACTION98
4.7828-6.02380.2144510.16298341X-RAY DIFFRACTION96
6.0238-46.4110.21354090.1928745X-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)
10.6128-0.12720.26371.8375-0.02261.77920.08390.1547-0.1895-0.0810.0124-0.14490.57290.2134-0.05420.49320.0309-0.03450.2859-0.07450.3145-29.4813-38.5378-75.8857
20.9444-0.2720.22540.75540.04532.2354-0.0403-0.1068-0.01890.14450.09380.0268-0.097-0.1111-0.04850.2486-0.0124-0.00240.17390.00750.2428-39.7846-15.2187-48.8412
30.7491-0.342-0.43061.55130.3722.16010.1799-0.26560.2936-0.08250.1742-0.3214-0.70470.4804-0.14330.5148-0.17630.11190.4355-0.17830.4302-1.141526.5779-85.6445
41.12290.3663-0.24291.39670.89812.17280.01350.09160.0191-0.28280.0917-0.0478-0.17770.0481-0.08780.27240.0315-0.00680.19080.00030.2435-11.22943.5554-113.1798
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 68:480)
2X-RAY DIFFRACTION2(chain B and resid 68:480)
3X-RAY DIFFRACTION3(chain C and resid 68:480)
4X-RAY DIFFRACTION4(chain D and resid 68:480)

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