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- PDB-6cie: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 6cie
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with N-(1-(2-(Ethyl(methyl)amino)ethyl)-1,2,3,4-tetrahydroquino-lin-6-yl)thiophene-2-carboximidamide
ComponentsNitric oxide synthase, endothelial
KeywordsOXIDOREDUCTASE / Nitric oxide synthase inhibitor complex heme enzyme
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-7R2 / 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: 1.95 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: Biochemistry / Year: 2018
Title: Structural Basis for Isoform Selective Nitric Oxide Synthase Inhibition by Thiophene-2-carboximidamides.
Authors: Li, H. / Evenson, R.J. / Chreifi, G. / Silverman, R.B. / Poulos, T.L.
History
DepositionFeb 23, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 31, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 7, 2018Group: Data collection / Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.identifier_ORCID
Revision 1.2Nov 21, 2018Group: Data collection / 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
Revision 1.3Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 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.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

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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)205,57139
Polymers197,3834
Non-polymers8,18835
Water7,062392
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A: Nitric oxide synthase, endothelial
B: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,89020
Polymers98,6922
Non-polymers4,19918
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11280 Å2
ΔGint-147 kcal/mol
Surface area34330 Å2
MethodPISA
2
C: Nitric oxide synthase, endothelial
D: Nitric oxide synthase, endothelial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,68119
Polymers98,6922
Non-polymers3,99017
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10860 Å2
ΔGint-155 kcal/mol
Surface area33290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.520, 152.230, 108.800
Angle α, β, γ (deg.)90.00, 90.48, 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 (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P29474, nitric-oxide synthase (NADPH)

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Non-polymers , 9 types, 427 molecules

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


Mass: 616.487 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
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-7R2 / N-(1-{2-[ethyl(methyl)amino]ethyl}-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide


Mass: 342.502 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H26N4S
#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.: 392 / 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: rods
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: 1.1271 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Feb 19, 2017 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1271 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 140506 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 4.1 % / CC1/2: 0.989 / Rmerge(I) obs: 0.212 / Rpim(I) all: 0.154 / Rsym value: 0.212 / Net I/σ(I): 7
Reflection shellResolution: 1.95→2 Å / Redundancy: 4 % / Rmerge(I) obs: 1.509 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 6965 / CC1/2: 0.524 / Rpim(I) all: 1.399 / Rsym value: 1.509 / % possible all: 99.9

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Processing

Software
NameVersionClassification
PHENIX(1.11.1-2575_1496: ???)refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DIP

4dip


Resolution: 1.95→45.987 Å / SU ML: 0.28 / Cross valid method: FREE R-VALUE / σ(F): 0.01 / Phase error: 34.77 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2618 13707 5.05 %random
Rwork0.2118 ---
obs0.2143 271341 97.45 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.95→45.987 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12824 0 512 392 13728
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00913807
X-RAY DIFFRACTIONf_angle_d1.01318816
X-RAY DIFFRACTIONf_dihedral_angle_d14.4848073
X-RAY DIFFRACTIONf_chiral_restr0.0541953
X-RAY DIFFRACTIONf_plane_restr0.0062422
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.95-1.97220.42484440.38158385X-RAY DIFFRACTION94
1.9722-1.99540.42564300.37378316X-RAY DIFFRACTION95
1.9954-2.01970.42284620.36448305X-RAY DIFFRACTION95
2.0197-2.04530.40234520.35528411X-RAY DIFFRACTION95
2.0453-2.07220.38265250.34728228X-RAY DIFFRACTION95
2.0722-2.10060.39654690.34568434X-RAY DIFFRACTION96
2.1006-2.13060.36174820.33188457X-RAY DIFFRACTION96
2.1306-2.16240.34954670.31398309X-RAY DIFFRACTION96
2.1624-2.19620.36563960.31178641X-RAY DIFFRACTION96
2.1962-2.23220.33864780.29328417X-RAY DIFFRACTION96
2.2322-2.27070.33913920.28538553X-RAY DIFFRACTION96
2.2707-2.3120.35374680.27748534X-RAY DIFFRACTION97
2.312-2.35640.29414550.26378477X-RAY DIFFRACTION97
2.3564-2.40450.32124460.26598560X-RAY DIFFRACTION97
2.4045-2.45680.33894760.25818614X-RAY DIFFRACTION97
2.4568-2.51390.30174810.25298554X-RAY DIFFRACTION98
2.5139-2.57680.27364250.24988703X-RAY DIFFRACTION98
2.5768-2.64650.30624960.24268508X-RAY DIFFRACTION98
2.6465-2.72430.27824970.23178687X-RAY DIFFRACTION98
2.7243-2.81230.29984230.23548670X-RAY DIFFRACTION98
2.8123-2.91280.26795130.23118600X-RAY DIFFRACTION99
2.9128-3.02940.30583800.22338832X-RAY DIFFRACTION99
3.0294-3.16720.29634260.21978847X-RAY DIFFRACTION99
3.1672-3.33410.29084800.20758740X-RAY DIFFRACTION100
3.3341-3.5430.23374860.1868748X-RAY DIFFRACTION100
3.543-3.81640.22914500.17128803X-RAY DIFFRACTION100
3.8164-4.20020.20144870.15958817X-RAY DIFFRACTION100
4.2002-4.80740.18584330.13838839X-RAY DIFFRACTION100
4.8074-6.05470.20694790.15848814X-RAY DIFFRACTION100
6.0547-46.00010.20244090.18918831X-RAY DIFFRACTION100
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)
10.93420.1314-0.6862.2329-0.43042.38310.36770.57940.32170.10080.20260.3632-0.9607-0.7406-0.24850.6270.26020.24140.62750.31860.488363.317931.8234-185.3581
21.1491-0.5567-0.24971.9493-0.84882.92430.0003-0.02780.04170.5170.11490.0042-0.2366-0.0723-0.11520.2801-0.0739-0.00540.2260.00940.284273.35838.4763-157.6882
30.7194-0.04790.33521.80780.10531.95280.1603-0.3027-0.32130.02620.0050.17560.7816-0.244-0.10050.6086-0.0432-0.10580.3820.12380.403592.0059-33.9301-195.2949
41.0780.49060.3020.85880.02462.9439-0.03040.0174-0.0472-0.21690.06790.0124-0.06860.1226-0.03740.33340.0791-0.03330.2056-0.00960.3038102.1597-10.3595-222.721
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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