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- PDB-7tsl: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 7tsl
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with 4-methyl-6-(3-(4-methylpiperazin-1-yl)propyl)pyridin-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 / 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 ATOM / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-KMR / 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)GM57353 United States
CitationJournal: Bioorg.Med.Chem. / Year: 2022
Title: 2-Aminopyridines with a shortened amino sidechain as potent, selective, and highly permeable human neuronal nitric oxide synthase inhibitors.
Authors: Vasu, D. / Li, H. / Hardy, C.D. / Poulos, T.L. / Silverman, R.B.
History
DepositionJan 31, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 13, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)205,26241
Polymers197,3834
Non-polymers7,87937
Water13,799766
1
A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,67721
Polymers98,6922
Non-polymers3,98519
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11510 Å2
ΔGint-153 kcal/mol
Surface area34500 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,58520
Polymers98,6922
Non-polymers3,89318
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10880 Å2
ΔGint-156 kcal/mol
Surface area33720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.277, 153.650, 109.077
Angle α, β, γ (deg.)90.000, 90.600, 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, 803 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-KMR / 4-methyl-6-[3-(4-methylpiperazin-1-yl)propyl]pyridin-2-amine


Mass: 248.367 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H24N4 / 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.: 5 / 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: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 766 / 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: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jan 20, 2021 / Details: mirrors
RadiationMonochromator: DOUBLE CRYSTAL SI(III) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.9→39.03 Å / Num. obs: 148370 / % possible obs: 95.5 % / Redundancy: 4.8 % / Biso Wilson estimate: 36.08 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.121 / Rpim(I) all: 0.06 / Rrim(I) all: 0.136 / Net I/σ(I): 5.5 / Num. measured all: 709558 / Scaling rejects: 1279
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.9-1.934.62.2973290971090.4211.1542.5790.792.7
10.41-39.034.90.05547349600.9960.0270.0621598

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Processing

Software
NameVersionClassification
Aimless0.7.4data scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 5UO8

5uo8


Resolution: 1.9→36.6751 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 0.95 / Phase error: 31.13 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2538 14577 5.04 %random
Rwork0.2036 274575 --
obs0.2061 147000 93.79 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 153.6 Å2 / Biso mean: 56.2234 Å2 / Biso min: 19.1 Å2
Refinement stepCycle: final / Resolution: 1.9→36.6751 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12848 0 492 766 14106
Biso mean--59.87 49.97 -
Num. residues----1608
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0113786
X-RAY DIFFRACTIONf_angle_d0.97818777
X-RAY DIFFRACTIONf_chiral_restr0.0551954
X-RAY DIFFRACTIONf_plane_restr0.0062410
X-RAY DIFFRACTIONf_dihedral_angle_d15.2748061
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 (%)
1.9003-1.92190.45213800.42457470785076
1.9219-1.94450.42884930.39429051954491
1.9445-1.96820.43044660.3788877934392
1.9682-1.99310.3814640.35739178964294
1.9931-2.01930.37134800.33879244972494
2.0193-2.0470.33535130.33499251976495
2.047-2.07620.35335010.32649299980095
2.0762-2.10720.33345660.31449073963995
2.1072-2.14010.3345170.30189120963793
2.1401-2.17520.33764460.29638474892087
2.1752-2.21270.33524490.28088682913189
2.2127-2.2530.29885270.26269358988597
2.253-2.29630.30284310.250696111004297
2.2963-2.34310.30225310.24699290982196
2.3431-2.39410.29214910.23919479997097
2.3941-2.44980.28175100.23119338984896
2.4498-2.5110.25735490.215194981004797
2.511-2.57890.25874450.21629390983596
2.5789-2.65480.26655270.2059337986495
2.6548-2.74040.27785330.21659098963194
2.7404-2.83830.28893930.22178361875486
2.8383-2.95190.2575280.20969470999897
2.9519-3.08620.28564450.213395741001998
3.0862-3.24880.27154790.208796121009198
3.2488-3.45220.25495210.18759438995997
3.4522-3.71850.24665030.17499382988596
3.7185-4.09230.19224620.15828767922990
4.0923-4.68340.18824770.13839316979395
4.6834-5.89670.19455300.145194951002597
5.8967-36.67510.2084200.17729042946292
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)
10.72250.1098-0.39922.2667-0.68621.94610.19430.44320.32120.13520.21030.4035-0.7055-0.5329-0.25030.59940.19290.13570.5120.23610.435664.46131.834-185.83
21.1505-0.3419-0.16031.5025-1.00982.6860.0332-0.06480.02570.27060.1240.0944-0.1901-0.1566-0.1450.3119-0.0474-0.0020.17090.00360.242674.6148.522-158.038
30.66530.15380.33551.8563-0.20632.03430.1167-0.2585-0.2350.04760.01880.13350.7818-0.1933-0.1010.751-0.003-0.05810.33620.09940.341893.613-34.209-195.895
40.9830.32640.28580.8414-0.00482.7036-0.03530.0348-0.0325-0.10820.1028-0.0088-0.01680.1252-0.07030.29230.0448-0.00790.1605-0.00620.2373104.008-10.429-223.161
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 68:480 )B68 - 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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