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- PDB-6nh1: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 6nh1
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with 6-(3-fluoro-5-(3-(methylamino)prop-1-yn-1-yl)phenethyl)-4-methylpyridin-2-amine
ComponentsEndothelial nitric oxide synthase splice variant eNOS13A
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE inhibitor / nitric oxide synthase inhibitor complex heme enzyme / OXIDOREDUCTASE / 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 / metal ion binding / 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
GADOLINIUM ATOM / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-KLY / nitric-oxide synthase (NADPH) / Nitric oxide synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.216 Å
AuthorsChreifi, G. / Li, H. / Poulos, T.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)GM57353 United States
CitationJournal: J. Med. Chem. / Year: 2019
Title: Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold.
Authors: Do, H.T. / Li, H. / Chreifi, G. / Poulos, T.L. / Silverman, R.B.
History
DepositionDec 21, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2019Group: 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 1.2Dec 4, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 11, 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_conn_type
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.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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_conn_type.id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Endothelial nitric oxide synthase splice variant eNOS13A
B: Endothelial nitric oxide synthase splice variant eNOS13A
C: Endothelial nitric oxide synthase splice variant eNOS13A
D: Endothelial nitric oxide synthase splice variant eNOS13A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)205,52241
Polymers197,3834
Non-polymers8,13937
Water3,117173
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A: Endothelial nitric oxide synthase splice variant eNOS13A
B: Endothelial nitric oxide synthase splice variant eNOS13A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,28423
Polymers98,6922
Non-polymers4,59221
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11310 Å2
ΔGint-151 kcal/mol
Surface area34350 Å2
MethodPISA
2
C: Endothelial nitric oxide synthase splice variant eNOS13A
D: Endothelial nitric oxide synthase splice variant eNOS13A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,23818
Polymers98,6922
Non-polymers3,54616
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11010 Å2
ΔGint-153 kcal/mol
Surface area33910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.264, 152.461, 108.816
Angle α, β, γ (deg.)90.00, 90.73, 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
Endothelial nitric oxide synthase splice variant eNOS13A


Mass: 49345.770 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line: endothelial / Plasmid: pCWori / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: A0S0A6, UniProt: P29474*PLUS

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Non-polymers , 9 types, 210 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-KLY / 6-(2-{3-fluoro-5-[3-(methylamino)prop-1-yn-1-yl]phenyl}ethyl)-4-methylpyridin-2-amine


Mass: 297.370 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H20FN3
#4: 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
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#7: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#8: Chemical
ChemComp-GD / GADOLINIUM ATOM


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


Mass: 18.015 Da / Num. of mol.: 173 / 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 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 15, 2017 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.216→60 Å / Num. obs: 95473 / % possible obs: 98.7 % / Observed criterion σ(I): -3 / Redundancy: 5.4 % / CC1/2: 0.959 / Rmerge(I) obs: 0.192 / Rpim(I) all: 0.09 / Rsym value: 0.192 / Net I/σ(I): 5.5
Reflection shellResolution: 2.22→2.26 Å / Redundancy: 4.7 % / Rmerge(I) obs: 2.313 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 4364 / CC1/2: 0.617 / Rpim(I) all: 1.263 / Rsym value: 2.313 / % possible all: 89.7

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Processing

Software
NameVersionClassification
PHENIX1.11.1-2575_1496refinement
MOSFLMdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4DIP

4dip


Resolution: 2.216→38.993 Å / SU ML: 0.44 / Cross valid method: FREE R-VALUE / σ(F): 0.89 / Phase error: 36.39
RfactorNum. reflection% reflectionSelection details
Rfree0.2795 9087 4.99 %random
Rwork0.2123 ---
obs0.2155 92157 96.17 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.216→38.993 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12895 0 506 173 13574
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01313880
X-RAY DIFFRACTIONf_angle_d1.14118901
X-RAY DIFFRACTIONf_dihedral_angle_d17.128109
X-RAY DIFFRACTIONf_chiral_restr0.0571959
X-RAY DIFFRACTIONf_plane_restr0.0072429
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2161-2.24130.44592720.46955401X-RAY DIFFRACTION90
2.2413-2.26770.4531900.43813950X-RAY DIFFRACTION65
2.2677-2.29530.45722840.41255340X-RAY DIFFRACTION90
2.2953-2.32440.38863150.38875439X-RAY DIFFRACTION92
2.3244-2.3550.42313070.38495627X-RAY DIFFRACTION93
2.355-2.38720.43452950.38565661X-RAY DIFFRACTION95
2.3872-2.42130.45973020.40035695X-RAY DIFFRACTION96
2.4213-2.45750.42553220.38985676X-RAY DIFFRACTION94
2.4575-2.49580.42443170.36175576X-RAY DIFFRACTION94
2.4958-2.53680.35632830.33185949X-RAY DIFFRACTION99
2.5368-2.58050.38833200.31065975X-RAY DIFFRACTION99
2.5805-2.62740.35193250.30145872X-RAY DIFFRACTION99
2.6274-2.67790.35933840.29535950X-RAY DIFFRACTION99
2.6779-2.73260.33192960.27735898X-RAY DIFFRACTION99
2.7326-2.7920.32163120.26975975X-RAY DIFFRACTION99
2.792-2.85690.35372980.27345900X-RAY DIFFRACTION99
2.8569-2.92830.33073370.26945965X-RAY DIFFRACTION99
2.9283-3.00750.34972710.26675902X-RAY DIFFRACTION99
3.0075-3.09590.40332800.24965953X-RAY DIFFRACTION99
3.0959-3.19580.30052820.23225833X-RAY DIFFRACTION97
3.1958-3.310.33873030.225871X-RAY DIFFRACTION98
3.31-3.44240.28823490.21135941X-RAY DIFFRACTION100
3.4424-3.5990.24973170.18495927X-RAY DIFFRACTION100
3.599-3.78860.26363090.16865999X-RAY DIFFRACTION100
3.7886-4.02570.20193050.15415980X-RAY DIFFRACTION99
4.0257-4.33620.22673250.14265913X-RAY DIFFRACTION99
4.3362-4.77190.21292830.13685816X-RAY DIFFRACTION97
4.7719-5.46080.21183280.13235971X-RAY DIFFRACTION99
5.4608-6.87390.23563010.15625954X-RAY DIFFRACTION100
6.8739-38.99870.19162750.1725928X-RAY DIFFRACTION98
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)
10.78030.2608-0.38431.6077-0.44471.98710.27960.38460.36270.18030.17470.338-0.7311-0.7252-0.23040.80690.22890.12530.69150.26320.532863.892331.2981-185.1956
21.0244-0.4972-0.42061.4422-0.6652.2655-0.0154-0.05970.04610.45430.10930.0136-0.2302-0.0868-0.18980.595-0.0597-0.0620.32480.00730.306773.94438.0617-157.6269
30.57790.01860.09951.6846-0.02061.71740.1237-0.1855-0.27880.02950.0220.1550.7285-0.21350.12230.9389-0.0441-0.16310.49930.08490.485192.6168-34.5368-195.4153
40.93910.33580.2650.76250.15232.3259-0.02240.0551-0.0833-0.25040.05690.01920.04250.05-0.06730.65930.0486-0.09820.3272-0.00640.3341102.9947-11.1185-222.8909
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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