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

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Basic information

Entry
Database: PDB / ID: 5vvb
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with 4-(2-(((2-Aminoquinolin-7-yl)methyl)amino)ethyl)-2-methylbenzonitrile
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 / 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 / lung development / cell redox homeostasis / 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 / cytoplasm / cytosol
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-9P7 / 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: 2.15 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.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
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)205,04937
Polymers197,3834
Non-polymers7,66633
Water9,404522
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A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,62919
Polymers98,6922
Non-polymers3,93717
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10970 Å2
ΔGint-153 kcal/mol
Surface area33330 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,42018
Polymers98,6922
Non-polymers3,72816
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10780 Å2
ΔGint-154 kcal/mol
Surface area33550 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.310, 153.050, 108.681
Angle α, β, γ (deg.)90.00, 90.75, 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, 555 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-9P7 / 4-(2-{[(2-aminoquinolin-7-yl)methyl]amino}ethyl)-2-methylbenzonitrile


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.: 9 / 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-GD / GADOLINIUM ATOM


Mass: 157.250 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Gd
#9: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 522 / 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: ALS / Beamline: 8.2.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 30, 2016 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.15→56 Å / Num. obs: 96561 / % possible obs: 92.6 % / Observed criterion σ(I): -3 / Redundancy: 2.7 % / CC1/2: 0.984 / Rmerge(I) obs: 0.151 / Rpim(I) all: 0.151 / Rsym value: 0.151 / Net I/σ(I): 4.2
Reflection shellResolution: 2.15→2.21 Å / Redundancy: 2.7 % / Rmerge(I) obs: 1.241 / Mean I/σ(I) obs: 0.8 / Num. unique obs: 4733 / CC1/2: 0.388 / Rpim(I) all: 1.241 / Rsym value: 1.241 / % possible all: 90.5

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
iMOSFLM7.2.1data reduction
Aimless0.5.17data scaling
REFMAC5.8.0049phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4D1P

4d1p


Resolution: 2.15→55.299 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 30.19
RfactorNum. reflection% reflectionSelection details
Rfree0.2676 9637 5.01 %random
Rwork0.2022 ---
obs0.2054 96448 92.45 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.15→55.299 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12831 0 484 522 13837
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913807
X-RAY DIFFRACTIONf_angle_d1.17318836
X-RAY DIFFRACTIONf_dihedral_angle_d16.5245021
X-RAY DIFFRACTIONf_chiral_restr0.0441951
X-RAY DIFFRACTIONf_plane_restr0.0052424
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.15-2.17440.4072780.31696027X-RAY DIFFRACTION91
2.1744-2.20.41443180.30876011X-RAY DIFFRACTION90
2.2-2.22690.31692800.29665962X-RAY DIFFRACTION91
2.2269-2.25510.34873020.30315941X-RAY DIFFRACTION91
2.2551-2.28470.35252770.29916098X-RAY DIFFRACTION91
2.2847-2.3160.35543520.28685985X-RAY DIFFRACTION92
2.316-2.34910.32873440.28736111X-RAY DIFFRACTION93
2.3491-2.38420.36873410.27726065X-RAY DIFFRACTION93
2.3842-2.42140.31423260.27196180X-RAY DIFFRACTION94
2.4214-2.46110.33593030.27366224X-RAY DIFFRACTION94
2.4611-2.50360.32293950.27286085X-RAY DIFFRACTION94
2.5036-2.54910.30562910.25926334X-RAY DIFFRACTION95
2.5491-2.59810.34453360.24266205X-RAY DIFFRACTION95
2.5981-2.65120.29423640.2376241X-RAY DIFFRACTION95
2.6512-2.70880.27413310.2286204X-RAY DIFFRACTION94
2.7088-2.77180.2953590.22516215X-RAY DIFFRACTION96
2.7718-2.84110.28263290.2166202X-RAY DIFFRACTION94
2.8411-2.91790.27183800.21276108X-RAY DIFFRACTION95
2.9179-3.00380.29743480.20926197X-RAY DIFFRACTION94
3.0038-3.10070.32172840.21186234X-RAY DIFFRACTION94
3.1007-3.21150.29142980.21176129X-RAY DIFFRACTION93
3.2115-3.34010.25123380.18766151X-RAY DIFFRACTION93
3.3401-3.49210.23873450.17686056X-RAY DIFFRACTION92
3.4921-3.67620.27633330.1716058X-RAY DIFFRACTION93
3.6762-3.90650.2193040.15686083X-RAY DIFFRACTION92
3.9065-4.2080.21173300.14955974X-RAY DIFFRACTION91
4.208-4.63130.19332860.13645948X-RAY DIFFRACTION90
4.6313-5.30090.20773220.14045902X-RAY DIFFRACTION90
5.3009-6.67680.22952580.16565853X-RAY DIFFRACTION88
6.6768-55.31690.21732850.19485820X-RAY DIFFRACTION88
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)
10.67310.08380.36231.144-0.24311.44350.1247-0.2295-0.19860.03080.02010.1060.4422-0.2521-0.03070.3837-0.0563-0.04180.26490.08960.299692.4312-34.1835-195.0943
20.64590.22770.22190.5621-0.01811.7869-0.03970.0483-0.019-0.09540.05950.0105-0.09120.1413-0.03070.21120.0286-0.0090.1747-0.00120.2257102.509-10.3342-222.4706
30.44540.3281-0.11461.2134-0.50151.02770.08620.25850.19510.01530.16210.2084-0.42-0.356-0.05080.34990.11920.07750.38260.15650.332863.764731.9607-185.4026
40.7703-0.1615-0.13771.095-0.65911.46690.0321-0.0551-0.01580.21730.05910.0122-0.0852-0.0641-0.06390.1336-0.0516-0.00560.17220.01410.205173.55638.7667-157.4971
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 68:480)
2X-RAY DIFFRACTION2(chain B and resid 68:480)
3X-RAY DIFFRACTION3(chain C and resid 68:480)
4X-RAY DIFFRACTION4(chain D and resid 67:480)

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