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- PDB-5uo8: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 5uo8
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with 3-[(2-aminoquinolin-7-yl)methoxy]-5-((methylamino)methyl)benzonitrile
ComponentsNitric oxide synthase, endothelial
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / nitric / oxide / synthase / inhibitor / complex / heme / enzyme / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


regulation of the force of heart contraction by chemical signal / NOSIP mediated eNOS trafficking / NOSTRIN mediated eNOS trafficking / negative regulation of muscle hyperplasia / regulation of nervous system process / smooth muscle hyperplasia / response to fluid shear stress / ovulation from ovarian follicle / pulmonary valve morphogenesis / negative regulation of biomineral tissue development ...regulation of the force of heart contraction by chemical signal / NOSIP mediated eNOS trafficking / NOSTRIN mediated eNOS trafficking / negative regulation of muscle hyperplasia / regulation of nervous system process / smooth muscle hyperplasia / response to fluid shear stress / ovulation from ovarian follicle / 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 / endothelial cell migration / nitric-oxide synthase (NADPH) / positive regulation of blood vessel endothelial cell migration / blood vessel remodeling / nitric-oxide synthase activity / eNOS activation / arginine catabolic process / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / regulation of sodium ion transport / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / nitric oxide mediated signal transduction / homeostasis of number of cells within a tissue / lipopolysaccharide-mediated signaling pathway / nitric oxide biosynthetic process / negative regulation of blood pressure / blood vessel diameter maintenance / removal of superoxide radicals / mitochondrion organization / VEGFR2 mediated vascular permeability / cell redox homeostasis / response to hormone / caveola / establishment of localization in cell / negative regulation of smooth muscle cell proliferation / lung development / potassium ion transport / regulation of blood pressure / vasodilation / positive regulation of angiogenesis / calcium ion transport / endocytic vesicle membrane / FMN binding / NADP binding / flavin adenine dinucleotide 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
Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / Nitric-oxide synthase, eukaryote / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily ...Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / Nitric-oxide synthase, eukaryote / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain 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 / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-8EV / 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 / MOLECULAR REPLACEMENT / Resolution: 2.18 Å
AuthorsChreifi, G. / Li, 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: 2017
Title: Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors.
Authors: Cinelli, M.A. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionJan 31, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2017Provider: repository / Type: Initial release
Revision 1.1May 24, 2017Group: Database references
Revision 1.2Sep 13, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr1_symmetry / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)204,70532
Polymers197,3834
Non-polymers7,32228
Water5,855325
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A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,35316
Polymers98,6922
Non-polymers3,66114
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10320 Å2
ΔGint-90 kcal/mol
Surface area33610 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,35316
Polymers98,6922
Non-polymers3,66114
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10490 Å2
ΔGint-88 kcal/mol
Surface area33520 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.370, 152.740, 108.511
Angle α, β, γ (deg.)90.00, 90.74, 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 / Fragment: UNP residues 41-480
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NOS3 / Organ: endothelial / Plasmid: pCWori / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P29474, nitric-oxide synthase (NADPH)

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Non-polymers , 8 types, 353 molecules

#2: Chemical
ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN / Tetrahydrobiopterin


Mass: 241.247 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#4: Chemical
ChemComp-8EV / 3-[(2-aminoquinolin-7-yl)methoxy]-5-[(methylamino)methyl]benzonitrile


Mass: 318.372 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H18N4O
#5: Chemical
ChemComp-BTB / 2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / BIS-TRIS BUFFER / Bis-tris methane


Mass: 209.240 Da / Num. of mol.: 8 / 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 / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#8: Chemical
ChemComp-GD / GADOLINIUM ATOM


Mass: 157.250 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Gd
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 325 / Source method: isolated from a natural source / Formula: H2O

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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: rice grain-like
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 12-15% PEG3350, 0.1 M Bis-Tris, 0.2-0.3 M magnesium acetate, 0.1 M gadolinium chloride, 10% glycerol, 5 mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 30, 2016 / Details: mirrors
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.18→60 Å / Num. obs: 90391 / % possible obs: 90.4 % / Observed criterion σ(I): -3 / Redundancy: 2.8 % / CC1/2: 0.986 / Rmerge(I) obs: 0.154 / Rpim(I) all: 0.154 / Rsym value: 0.154 / Net I/σ(I): 20.8
Reflection shellResolution: 2.18→2.24 Å / Redundancy: 2.8 % / Rmerge(I) obs: 1.975 / Mean I/σ(I) obs: 1.2 / Num. unique all: 4538 / CC1/2: 0.368 / Rpim(I) all: 1.969 / Rsym value: 1.975 / % possible all: 91.8

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
iMOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4D1P

4d1p


Resolution: 2.18→49.535 Å / SU ML: 0.33 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 33.62
RfactorNum. reflection% reflectionSelection details
Rfree0.2721 4482 4.99 %random
Rwork0.2062 ---
obs0.2096 89674 89.44 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.18→49.535 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12846 0 466 325 13637
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913791
X-RAY DIFFRACTIONf_angle_d1.18218812
X-RAY DIFFRACTIONf_dihedral_angle_d16.6775006
X-RAY DIFFRACTIONf_chiral_restr0.0451948
X-RAY DIFFRACTIONf_plane_restr0.0062422
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.18-2.20480.38662640.32495744X-RAY DIFFRACTION90
2.2048-2.23070.33843170.3075547X-RAY DIFFRACTION90
2.2307-2.25790.40182880.31015744X-RAY DIFFRACTION90
2.2579-2.28650.36992910.30325747X-RAY DIFFRACTION91
2.2865-2.31660.40043100.30095645X-RAY DIFFRACTION90
2.3166-2.34830.37723220.30395640X-RAY DIFFRACTION90
2.3483-2.38190.37622640.29765794X-RAY DIFFRACTION91
2.3819-2.41740.34523080.28465668X-RAY DIFFRACTION91
2.4174-2.45520.35163110.27675730X-RAY DIFFRACTION90
2.4552-2.49540.33853160.28145685X-RAY DIFFRACTION91
2.4954-2.53850.36022790.27415710X-RAY DIFFRACTION91
2.5385-2.58460.34793200.26375765X-RAY DIFFRACTION91
2.5846-2.63430.31823300.25335643X-RAY DIFFRACTION91
2.6343-2.68810.31313330.24785769X-RAY DIFFRACTION91
2.6881-2.74660.33542880.2465619X-RAY DIFFRACTION90
2.7466-2.81040.31622740.24535792X-RAY DIFFRACTION91
2.8104-2.88070.29873040.23265659X-RAY DIFFRACTION90
2.8807-2.95860.28853020.21145680X-RAY DIFFRACTION90
2.9586-3.04560.32673120.20755605X-RAY DIFFRACTION90
3.0456-3.14390.31032840.22265693X-RAY DIFFRACTION90
3.1439-3.25630.27142890.21575623X-RAY DIFFRACTION89
3.2563-3.38660.25472950.19225650X-RAY DIFFRACTION89
3.3866-3.54070.25643130.17735573X-RAY DIFFRACTION89
3.5407-3.72730.22312540.16565635X-RAY DIFFRACTION88
3.7273-3.96080.22372860.1545533X-RAY DIFFRACTION88
3.9608-4.26640.21262820.14965530X-RAY DIFFRACTION88
4.2664-4.69550.20752740.13265343X-RAY DIFFRACTION85
4.6955-5.37420.17963110.1395493X-RAY DIFFRACTION87
5.3742-6.76820.23942900.16265409X-RAY DIFFRACTION86
6.7682-49.54760.20852690.19625307X-RAY DIFFRACTION84
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)
10.62980.2117-0.46741.89-0.38731.68310.14970.30180.23-0.06990.16030.3248-0.637-0.5478-0.16010.43590.1580.08250.45520.15730.348863.496932.0603-184.8905
21.1398-0.2844-0.15171.2583-0.74372.36680.03-0.12660.01750.31160.0303-0.0516-0.1529-0.0578-0.06730.2341-0.0961-0.00270.1916-0.00150.247373.62988.657-157.2125
30.81930.0930.38021.9921-0.02281.48340.1267-0.2249-0.21120.2022-0.01350.14950.4777-0.322-0.0770.4272-0.0341-0.02810.31730.06570.288392.1362-34.1652-194.747
41.00910.39250.36630.7574-0.13222.4356-0.0880.0939-0.0075-0.15790.08890.0007-0.04290.0891-0.00410.27620.0604-0.0230.1618-0.01340.2379102.34-10.3524-222.1208
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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