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

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Basic information

Entry
Database: PDB / ID: 5uoa
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with 3-[(2-Amino-4-methylquinolin-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 platelet activation / negative regulation of calcium ion transport / actin monomer binding / endothelial cell migration / removal of superoxide radicals / nitric-oxide synthase (NADPH) / positive regulation of blood vessel endothelial cell migration / blood vessel remodeling / nitric-oxide synthase activity / eNOS activation / nitric oxide mediated signal transduction / arginine catabolic process / homeostasis of number of cells within a tissue / regulation of sodium ion transport / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / lipopolysaccharide-mediated signaling pathway / nitric oxide biosynthetic process / negative regulation of blood pressure / blood vessel diameter maintenance / mitochondrion organization / response to hormone / cell redox homeostasis / VEGFR2 mediated vascular permeability / caveola / negative regulation of smooth muscle cell proliferation / establishment of localization in cell / lung development / potassium ion transport / regulation of blood pressure / vasodilation / endocytic vesicle membrane / positive regulation of angiogenesis / calcium ion transport / 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
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-8EY / GADOLINIUM ATOM / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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 27, 2017Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 1, 2020Group: 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
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.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.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

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,60224
Polymers98,6922
Non-polymers4,91022
Water1,04558
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10730 Å2
ΔGint-187 kcal/mol
Surface area34590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)57.476, 109.662, 154.051
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#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.: 2 / Fragment: UNP residues 41-480
Source method: isolated from a genetically manipulated source
Details: Residues 108 to 118 are disordered. The N-terminal residues 41 to 67 are invisible in density.
Source: (gene. exp.) Homo sapiens (human) / Cell: endothelial / Gene: NOS3 / Plasmid: pCWori / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P29474, nitric-oxide synthase (NADPH)

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Non-polymers , 8 types, 80 molecules

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


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-8EY / 3-[(2-amino-4-methylquinolin-7-yl)methoxy]-5-[(methylamino)methyl]benzonitrile


Mass: 332.399 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H20N4O
#4: 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
#5: Chemical ChemComp-ZN / ZINC ION


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


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical ChemComp-GD / GADOLINIUM ATOM


Mass: 157.250 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Gd
#8: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 58 / 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 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 12-15% 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
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL14-1 / Wavelength: 1.1808 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Dec 16, 2015 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1808 Å / Relative weight: 1
ReflectionResolution: 2.15→50 Å / Num. obs: 53833 / % possible obs: 99.7 % / Observed criterion σ(I): -3 / Redundancy: 4.1 % / CC1/2: 0.998 / Rmerge(I) obs: 0.09 / Rpim(I) all: 0.078 / Rsym value: 0.09 / Net I/σ(I): 5.5
Reflection shellResolution: 2.15→2.25 Å / Redundancy: 4 % / Rmerge(I) obs: 2.782 / Mean I/σ(I) obs: 0.2 / Num. unique obs: 4442 / CC1/2: 0.273 / Rpim(I) all: 2.373 / Rsym value: 2.782 / % possible all: 96.3

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Processing

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

4d1p


Resolution: 2.2→38.513 Å / SU ML: 0.46 / Cross valid method: FREE R-VALUE / σ(F): 1.04 / Phase error: 38.99
RfactorNum. reflection% reflectionSelection details
Rfree0.2805 4565 4.88 %ramdom
Rwork0.2226 ---
obs0.2255 93548 97.99 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.2→38.513 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6409 0 311 58 6778
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0126980
X-RAY DIFFRACTIONf_angle_d1.1949503
X-RAY DIFFRACTIONf_dihedral_angle_d17.6312541
X-RAY DIFFRACTIONf_chiral_restr0.05977
X-RAY DIFFRACTIONf_plane_restr0.0061215
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.2250.54121330.46462661X-RAY DIFFRACTION88
2.225-2.25120.43621440.45862771X-RAY DIFFRACTION92
2.2512-2.27860.42371730.43472858X-RAY DIFFRACTION95
2.2786-2.30750.48641550.43652945X-RAY DIFFRACTION97
2.3075-2.33780.42641390.41472931X-RAY DIFFRACTION98
2.3378-2.36990.4411510.41362956X-RAY DIFFRACTION98
2.3699-2.40370.45841410.39833022X-RAY DIFFRACTION98
2.4037-2.43960.39481490.38952984X-RAY DIFFRACTION98
2.4396-2.47770.42281280.36172987X-RAY DIFFRACTION99
2.4777-2.51830.39651410.34743012X-RAY DIFFRACTION98
2.5183-2.56170.42311930.33592931X-RAY DIFFRACTION99
2.5617-2.60830.41421400.33583059X-RAY DIFFRACTION99
2.6083-2.65850.36091460.31622934X-RAY DIFFRACTION98
2.6585-2.71270.39421800.30852927X-RAY DIFFRACTION98
2.7127-2.77170.41721430.28213012X-RAY DIFFRACTION99
2.7717-2.83610.34331550.28612995X-RAY DIFFRACTION99
2.8361-2.9070.33221600.26662998X-RAY DIFFRACTION99
2.907-2.98560.3041390.24742993X-RAY DIFFRACTION99
2.9856-3.07340.30541570.22972988X-RAY DIFFRACTION99
3.0734-3.17260.3231580.23632999X-RAY DIFFRACTION99
3.1726-3.28590.27741620.22172945X-RAY DIFFRACTION99
3.2859-3.41740.31091370.21553060X-RAY DIFFRACTION99
3.4174-3.57280.25781710.20522973X-RAY DIFFRACTION99
3.5728-3.76110.22671530.18972976X-RAY DIFFRACTION99
3.7611-3.99650.27351410.1813028X-RAY DIFFRACTION99
3.9965-4.30470.24391520.16252995X-RAY DIFFRACTION99
4.3047-4.73720.21731610.14573019X-RAY DIFFRACTION99
4.7372-5.4210.19661700.15432973X-RAY DIFFRACTION99
5.421-6.82370.23721420.17733043X-RAY DIFFRACTION99
6.8237-38.51860.21431510.18223008X-RAY DIFFRACTION99
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)
10.6846-0.3578-0.05261.90040.10693.01160.26120.2890.1994-1.2098-0.2064-0.40630.01910.1219-0.08131.11440.14960.11030.46460.05410.5588-14.769522.4904-33.8762
21.3981-0.5083-0.46113.02410.19591.9569-0.09070.0261-0.3021-0.1598-0.0072-0.03611.0780.0790.09061.06710.0683-0.10290.3877-0.03350.4069-24.715-5.3703-9.8077
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)

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