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

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Basic information

Entry
Database: PDB / ID: 8ufr
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with 4-methyl-7-(4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-7-yl)quinolin-2-amine dihydrochloride
ComponentsNitric oxide synthase, endothelial
KeywordsOXIDOREDUCTASE / nitric oxide synthase inhibitor / heme enzyme
Function / homology
Function and homology information


negative regulation of muscle hyperplasia / regulation of the force of heart contraction by chemical signal / NOSIP mediated eNOS trafficking / 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 ...negative regulation of muscle hyperplasia / regulation of the force of heart contraction by chemical signal / NOSIP mediated eNOS trafficking / 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 / positive regulation of guanylate cyclase activity / 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 potassium ion transport / negative regulation of calcium ion transport / nitric oxide mediated signal transduction / negative regulation of platelet activation / actin monomer binding / 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 / regulation of sodium ion transport / eNOS activation / nitric oxide metabolic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / negative regulation of blood pressure / homeostasis of number of cells within a tissue / response to hormone / nitric oxide biosynthetic process / removal of superoxide radicals / cell redox homeostasis / lipopolysaccharide-mediated signaling pathway / blood vessel diameter maintenance / VEGFR2 mediated vascular permeability / mitochondrion organization / establishment of localization in cell / negative regulation of smooth muscle cell proliferation / lung development / potassium ion transport / caveola / regulation of blood pressure / positive regulation of angiogenesis / calcium ion transport / vasodilation / endocytic vesicle membrane / FMN binding / flavin adenine dinucleotide binding / NADP binding / response to heat / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / scaffold protein binding / angiogenesis / response to lipopolysaccharide / in utero embryonic development / cytoskeleton / Extra-nuclear estrogen signaling / calmodulin binding / 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: 1.871 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: Biochemistry / Year: 2024
Title: Crystallographic and Computational Insights into Isoform-Selective Dynamics in Nitric Oxide Synthase.
Authors: Li, H. / Hardy, C.D. / Reidl, C.T. / Jing, Q. / Xue, F. / Cinelli, M. / Silverman, R.B. / Poulos, T.L.
History
DepositionOct 4, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)205,47939
Polymers197,3834
Non-polymers8,09635
Water8,431468
1
A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,84420
Polymers98,6922
Non-polymers4,15318
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10950 Å2
ΔGint-149 kcal/mol
Surface area33950 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,63519
Polymers98,6922
Non-polymers3,94317
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11020 Å2
ΔGint-152 kcal/mol
Surface area33690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.491, 152.859, 108.942
Angle α, β, γ (deg.)90.00, 90.86, 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, 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, 503 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-WK2 / (7M)-4-methyl-7-(4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)quinolin-2-amine


Mass: 319.400 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H21N3O / 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-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / 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.: 4 / Source method: obtained synthetically / Formula: Gd
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 468 / 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: 2.51 Å3/Da / Density % sol: 50.98 % / 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: Dec 2, 2018 / Details: mirror
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.87→39.12 Å / Num. obs: 157245 / % possible obs: 98 % / Redundancy: 4.7 % / CC1/2: 0.995 / Rmerge(I) obs: 0.122 / Rpim(I) all: 0.062 / Rrim(I) all: 0.137 / Χ2: 0.91 / Net I/σ(I): 6.3 / Num. measured all: 733024
Reflection shellResolution: 1.87→1.9 Å / % possible obs: 93.1 % / Redundancy: 4.2 % / Rmerge(I) obs: 4.185 / Num. measured all: 30869 / Num. unique obs: 7360 / CC1/2: 0.285 / Rpim(I) all: 2.247 / Rrim(I) all: 4.775 / Χ2: 0.84 / Net I/σ(I) obs: 0.6

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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: 1.871→39.12 Å / SU ML: 0.3 / Cross valid method: FREE R-VALUE / σ(F): 0.7 / Phase error: 33.3 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.251 14495 5 %random
Rwork0.2071 ---
obs0.2093 146488 91.45 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.871→39.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12815 0 512 468 13795
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0113801
X-RAY DIFFRACTIONf_angle_d1.08818821
X-RAY DIFFRACTIONf_dihedral_angle_d14.7848046
X-RAY DIFFRACTIONf_chiral_restr0.0571952
X-RAY DIFFRACTIONf_plane_restr0.0062413
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.871-1.89190.61241140.55372998X-RAY DIFFRACTION30
1.8919-1.91410.47891660.49164017X-RAY DIFFRACTION39
1.9141-1.93750.46722910.44755837X-RAY DIFFRACTION58
1.9375-1.9620.43824180.4118103X-RAY DIFFRACTION81
1.962-1.98780.43424430.38328979X-RAY DIFFRACTION88
1.9878-2.0150.42245240.36799342X-RAY DIFFRACTION94
2.015-2.04380.34655370.35929758X-RAY DIFFRACTION97
2.0438-2.07430.35985830.33139695X-RAY DIFFRACTION98
2.0743-2.10670.3645410.31949893X-RAY DIFFRACTION98
2.1067-2.14130.34335540.30869751X-RAY DIFFRACTION98
2.1413-2.17820.32935290.29599836X-RAY DIFFRACTION98
2.1782-2.21780.32064870.28529893X-RAY DIFFRACTION98
2.2178-2.26050.3225150.27629693X-RAY DIFFRACTION97
2.2605-2.30660.31434680.26279577X-RAY DIFFRACTION95
2.3066-2.35670.29675410.26169780X-RAY DIFFRACTION98
2.3567-2.41160.2855170.23989901X-RAY DIFFRACTION99
2.4116-2.47190.3025610.23189935X-RAY DIFFRACTION99
2.4719-2.53870.27635040.21649843X-RAY DIFFRACTION99
2.5387-2.61340.25635500.20749906X-RAY DIFFRACTION99
2.6134-2.69770.24365810.20429923X-RAY DIFFRACTION99
2.6977-2.79410.25525020.20759885X-RAY DIFFRACTION99
2.7941-2.90590.26735350.23029808X-RAY DIFFRACTION98
2.9059-3.03810.29094460.21799675X-RAY DIFFRACTION96
3.0381-3.19820.27154920.20929987X-RAY DIFFRACTION99
3.1982-3.39850.26155470.19919983X-RAY DIFFRACTION99
3.3985-3.66070.23965220.18299911X-RAY DIFFRACTION99
3.6607-4.02880.19735240.156510007X-RAY DIFFRACTION99
4.0288-4.6110.16975020.13919611X-RAY DIFFRACTION96
4.611-5.80630.1895490.14429937X-RAY DIFFRACTION99
5.8063-39.120.19794520.17489883X-RAY DIFFRACTION98
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)
11.00340.2489-0.78532.3425-0.67342.51720.33480.55780.43690.17120.24560.4337-0.846-0.8089-0.40890.65860.27770.18970.59720.30420.491864.39431.906-185.634
21.2925-0.3638-0.5061.6363-0.77012.9090.0445-0.0830.05210.40370.07370.0024-0.1783-0.0707-0.10890.3849-0.0877-0.0350.17390.01330.239174.4548.497-157.929
30.68240.01620.38592.05640.05751.77920.1498-0.2615-0.28820.14180.01030.18030.6559-0.2368-0.1380.7095-0.0242-0.0980.34420.10540.363693.115-34.043-195.54
41.22010.40010.22961.0069-0.11552.6237-0.04270.0686-0.0453-0.20550.0863-0.02270.0060.163-0.04680.40270.0674-0.02720.1666-0.01240.2204103.471-10.411-223.006
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 67:480 )D67 - 480

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