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

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Basic information

Entry
Database: PDB / ID: 5vvd
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with 4-(2-(((2-Amino-4-methylquinolin-7-yl)methyl)amino)ethyl)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 / 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
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, N-terminal / Nitric oxide synthase, N-terminal domain superfamily / Nitric oxide synthase, domain 2 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, 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 / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-9OG / 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: 2.25 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: 2017
Title: Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.
Authors: Pensa, A.V. / Cinelli, M.A. / Li, H. / Chreifi, G. / Mukherjee, P. / Roman, L.J. / Martasek, P. / Poulos, T.L. / Silverman, R.B.
History
DepositionMay 19, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 16, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 6, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Sep 20, 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.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

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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)205,46739
Polymers197,3834
Non-polymers8,08435
Water1,60389
1
A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,20522
Polymers98,6922
Non-polymers4,51320
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11110 Å2
ΔGint-149 kcal/mol
Surface area34710 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,26217
Polymers98,6922
Non-polymers3,57115
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10920 Å2
ΔGint-155 kcal/mol
Surface area33630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.335, 153.135, 109.241
Angle α, β, γ (deg.)90.00, 90.78, 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: residues 41-480
Source method: isolated from a genetically manipulated source
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 , 9 types, 124 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-9OG / 4-(2-{[(2-amino-4-methylquinolin-7-yl)methyl]amino}ethyl)benzonitrile


Mass: 316.400 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C20H20N4
#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.: 89 / 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
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
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: BL9-2 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Feb 27, 2016 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.19→50 Å / Num. obs: 97368 / % possible obs: 97.8 % / Observed criterion σ(I): -3 / Redundancy: 3.1 % / CC1/2: 0.996 / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.073 / Rsym value: 0.109 / Net I/σ(I): 6
Reflection shellResolution: 2.19→2.25 Å / Redundancy: 2.9 % / Rmerge(I) obs: 2.917 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 4213 / CC1/2: 0.28 / Rpim(I) all: 2.009 / Rsym value: 2.917 / % possible all: 86.1

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSOct 15, 2015data reduction
Aimless0.5.17data scaling
REFMAC5.8.0049phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4DIP

4dip


Resolution: 2.25→39.117 Å / SU ML: 0.45 / Cross valid method: FREE R-VALUE / σ(F): 0.98 / Phase error: 36.02
RfactorNum. reflection% reflectionSelection details
Rfree0.2689 8305 5.01 %random
Rwork0.2064 ---
obs0.2095 86050 90.8 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.25→39.117 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12846 0 512 89 13447
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0113850
X-RAY DIFFRACTIONf_angle_d1.27518888
X-RAY DIFFRACTIONf_dihedral_angle_d17.3195042
X-RAY DIFFRACTIONf_chiral_restr0.0491958
X-RAY DIFFRACTIONf_plane_restr0.0062426
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.25-2.27560.42111840.43513915X-RAY DIFFRACTION67
2.2756-2.30230.50892100.43253761X-RAY DIFFRACTION66
2.3023-2.33040.4452250.41454154X-RAY DIFFRACTION72
2.3304-2.35990.45612330.40554276X-RAY DIFFRACTION73
2.3599-2.3910.42812540.3854786X-RAY DIFFRACTION83
2.391-2.42370.43612810.37155143X-RAY DIFFRACTION89
2.4237-2.45830.4492290.34744584X-RAY DIFFRACTION79
2.4583-2.4950.40352460.33954930X-RAY DIFFRACTION85
2.495-2.5340.37382960.32775317X-RAY DIFFRACTION93
2.534-2.57550.34112340.32975704X-RAY DIFFRACTION96
2.5755-2.61990.34463280.30995465X-RAY DIFFRACTION97
2.6199-2.66760.38933100.29865578X-RAY DIFFRACTION96
2.6676-2.71890.35192920.2985577X-RAY DIFFRACTION97
2.7189-2.77430.34512920.28125555X-RAY DIFFRACTION97
2.7743-2.83460.34772710.28995628X-RAY DIFFRACTION96
2.8346-2.90060.32913030.25975571X-RAY DIFFRACTION97
2.9006-2.97310.32342920.25595575X-RAY DIFFRACTION96
2.9731-3.05340.31672630.23815512X-RAY DIFFRACTION96
3.0534-3.14320.35552730.24895600X-RAY DIFFRACTION96
3.1432-3.24470.31392480.23965205X-RAY DIFFRACTION90
3.2447-3.36060.31593130.21495524X-RAY DIFFRACTION96
3.3606-3.4950.2763410.19895676X-RAY DIFFRACTION98
3.495-3.6540.26833130.1845619X-RAY DIFFRACTION98
3.654-3.84650.24633000.16455577X-RAY DIFFRACTION97
3.8465-4.08720.22143120.15425561X-RAY DIFFRACTION97
4.0872-4.40240.20643170.14455593X-RAY DIFFRACTION97
4.4024-4.84470.17532600.13035260X-RAY DIFFRACTION91
4.8447-5.54410.21573250.14025600X-RAY DIFFRACTION97
5.5441-6.97850.22022970.16225649X-RAY DIFFRACTION98
6.9785-39.12270.19352630.17635504X-RAY DIFFRACTION95
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)
11.43560.4734-0.89482.5496-0.4472.90.37950.38970.49720.22370.17110.4563-0.9982-0.8029-0.26670.62970.27660.20120.61540.20780.593563.980533.465-185.9309
21.1512-0.4365-0.55121.5497-0.63353.1840.0227-0.06810.03850.45180.03360.065-0.2393-0.1175-0.05830.454-0.13460.00040.3027-0.00810.409374.039.6602-158.4133
30.65030.16130.22433.32680.43072.17710.1247-0.1581-0.21830.0581-0.06110.24320.7555-0.2447-0.03520.6403-0.0586-0.10140.38310.04280.427292.42-33.1218-196.0375
41.0290.49120.97170.95750.10554.5576-0.11280.1242-0.0417-0.35590.12820.00370.08680.17710.00230.49240.0515-0.02560.2679-0.02120.3782102.7879-9.3978-223.6738
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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