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- PDB-8fgq: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 8fgq
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with 4-(5-(2-(dimethylamino)ethyl)-2,3-difluorophenethyl)-6-methylpyrimidin-2-amine
ComponentsNitric oxide synthase, endothelial
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor / heme enzyme
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 / NOSTRIN mediated eNOS trafficking / smooth muscle hyperplasia / regulation of nervous system process / ovulation from ovarian follicle / response to fluid shear stress / pulmonary valve morphogenesis / negative regulation of biomineral tissue development ...regulation of the force of heart contraction by chemical signal / NOSIP mediated eNOS trafficking / negative regulation of muscle hyperplasia / NOSTRIN mediated eNOS trafficking / smooth muscle hyperplasia / regulation of nervous system process / ovulation from ovarian follicle / response to fluid shear stress / pulmonary valve morphogenesis / negative regulation of biomineral tissue development / positive regulation of guanylate cyclase activity / 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 potassium ion transport / negative regulation of calcium ion transport / actin monomer binding / negative regulation of platelet activation / blood vessel remodeling / nitric-oxide synthase (NADPH) / endothelial cell migration / positive regulation of blood vessel endothelial cell migration / nitric oxide mediated signal transduction / nitric-oxide synthase activity / eNOS activation / arginine catabolic process / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / lipopolysaccharide-mediated signaling pathway / regulation of sodium ion transport / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / homeostasis of number of cells within a tissue / nitric oxide biosynthetic process / negative regulation of blood pressure / removal of superoxide radicals / response to hormone / cell redox homeostasis / blood vessel diameter maintenance / VEGFR2 mediated vascular permeability / establishment of localization in cell / mitochondrion organization / negative regulation of smooth muscle cell proliferation / lung development / potassium ion transport / caveola / regulation of blood pressure / vasodilation / positive regulation of angiogenesis / calcium ion transport / endocytic vesicle membrane / FMN binding / flavin adenine dinucleotide binding / NADP binding / response to heat / scaffold protein binding / angiogenesis / in utero embryonic development / response to lipopolysaccharide / Extra-nuclear estrogen signaling / cytoskeleton / calmodulin binding / negative regulation of cell population proliferation / Golgi membrane / 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 / Chem-V80 / Nitric oxide synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.2 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)GM57353 United States
CitationJournal: J.Med.Chem. / Year: 2023
Title: Potent, Selective, and Membrane Permeable 2-Amino-4-Substituted Pyridine-Based Neuronal Nitric Oxide Synthase Inhibitors.
Authors: Vasu, D. / Do, H.T. / Li, H. / Hardy, C.D. / Awasthi, A. / Poulos, T.L. / Silverman, R.B.
History
DepositionDec 12, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 11, 2023Provider: 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)205,39138
Polymers197,3834
Non-polymers8,00834
Water11,476637
1
A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,75419
Polymers98,6922
Non-polymers4,06217
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11110 Å2
ΔGint-153 kcal/mol
Surface area33860 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,63719
Polymers98,6922
Non-polymers3,94517
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10590 Å2
ΔGint-160 kcal/mol
Surface area32570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.569, 151.480, 108.348
Angle α, β, γ (deg.)90.000, 91.080, 90.000
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, 671 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 / Comment: neurotransmitter*YM
#4: Chemical
ChemComp-V80 / 4-(2-{5-[2-(dimethylamino)ethyl]-2,3-difluorophenyl}ethyl)-6-methylpyrimidin-2-amine


Mass: 320.380 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H22F2N4 / 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.: 11 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 637 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 24, 2020 / 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: 2.2→75.7849 Å / Num. obs: 97129 / % possible obs: 99.9 % / Redundancy: 3.6 % / Biso Wilson estimate: 27.9 Å2 / CC1/2: 0.966 / Rmerge(I) obs: 0.172 / Rpim(I) all: 0.106 / Rrim(I) all: 0.203 / Net I/σ(I): 5
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.6 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.2-2.241.2781728647550.3120.7811.51.299.9
12.05-75.740.08722456190.9830.0520.10211.599.7

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
MOSFLMdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 5UO8

5uo8


Resolution: 2.2→75.7849 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 27.67 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2462 9416 4.99 %random
Rwork0.1925 179329 --
obs0.1951 97007 98.2 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 148.9 Å2 / Biso mean: 45.4087 Å2 / Biso min: 11.39 Å2
Refinement stepCycle: final / Resolution: 2.2→75.7849 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12813 0 502 637 13952
Biso mean--60.62 41.54 -
Num. residues----1605
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913778
X-RAY DIFFRACTIONf_angle_d1.0618789
X-RAY DIFFRACTIONf_chiral_restr0.0541952
X-RAY DIFFRACTIONf_plane_restr0.0062412
X-RAY DIFFRACTIONf_dihedral_angle_d15.7628039
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2-2.2250.32953540.30385928628299
2.225-2.25120.38912910.3235918620998
2.2512-2.27860.34042740.29496071634598
2.2786-2.30750.34813450.27286002634799
2.3075-2.33780.32993240.27555935625999
2.3378-2.36990.33032760.27166076635298
2.3699-2.40370.33893440.27176022636699
2.4037-2.43960.32463150.26925894620998
2.4396-2.47770.31443640.25496014637898
2.4777-2.51840.31153000.24535919621998
2.5184-2.56180.27563030.24216036633998
2.5618-2.60840.29613310.23065956628798
2.6084-2.65850.26973620.22755962632498
2.6585-2.71280.27313350.22516040637598
2.7128-2.77180.2882980.21535919621798
2.7718-2.83630.2633150.21166044635998
2.8363-2.90720.27913440.20385891623598
2.9072-2.98580.30792680.20316032630098
2.9858-3.07370.25662640.19175998626298
3.0737-3.17290.26232930.19986004629798
3.1729-3.28630.24033140.17855958627298
3.2863-3.41790.24013400.17365884622498
3.4179-3.57340.23173110.16525900621197
3.5734-3.76180.22483210.16175975629697
3.7618-3.99750.17953050.14825956626197
3.9975-4.30610.18493150.13915838615397
4.3061-4.73940.18982940.13355994628899
4.7394-5.4250.20393310.14716082641399
5.425-6.83430.22142990.16575993629299
6.8343-75.78490.18682860.184560886374100
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)
10.84110.2267-0.56331.0749-0.35851.59810.26440.440.32750.08040.21140.2509-0.5971-0.5164-0.01690.41570.20680.15970.3860.28080.375465.49831.637-184.777
21.0176-0.2111-0.41031.066-0.37221.76530.066-0.03240.0480.1480.03660.0133-0.1199-0.0323-0.06230.1446-0.0513-0.00840.13050.01720.17875.1478.412-157.072
30.72580.09520.54451.40090.00231.37360.1716-0.2583-0.19170.05810.01460.16980.4745-0.1339-0.01790.39-0.0203-0.05140.19320.10820.276894.303-33.801-194.455
40.82260.26960.38330.59590.10521.8558-0.02550.03-0.0284-0.0650.0538-0.0177-0.05480.135-0.02360.16630.0373-0.0060.1286-0.00210.1801104.591-10.232-221.732
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 68:480 )D68 - 480

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