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- PDB-6nh5: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 6nh5
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with 6-(3-fluoro-5-(2-((2R,4S)-4-fluoro-1-methylpyrrolidin-2-yl)ethyl)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-KLD / nitric-oxide synthase (NADPH) / Nitric oxide synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.959 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
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: 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)205,87441
Polymers197,3834
Non-polymers8,49137
Water10,953608
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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)103,25122
Polymers98,6922
Non-polymers4,55920
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11830 Å2
ΔGint-133 kcal/mol
Surface area34620 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)102,62319
Polymers98,6922
Non-polymers3,93217
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10450 Å2
ΔGint-148 kcal/mol
Surface area32900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)59.528, 152.760, 108.980
Angle α, β, γ (deg.)90.00, 90.76, 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) / Strain (production host): BL21(DE3) / References: UniProt: A0S0A6, UniProt: P29474*PLUS

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Non-polymers , 9 types, 645 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-KLD / 6-[2-(3-fluoro-5-{2-[(2R,4S)-4-fluoro-1-methylpyrrolidin-2-yl]ethyl}phenyl)ethyl]-4-methylpyridin-2-amine


Mass: 359.456 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H27F2N3
#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.: 13 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#6: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / 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.: 2 / Source method: obtained synthetically / Formula: Gd
#10: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 608 / 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: 5.0.2 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: May 28, 2017 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.959→90 Å / Num. obs: 139289 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 5.6 % / CC1/2: 0.997 / Rmerge(I) obs: 0.133 / Rpim(I) all: 0.092 / Rsym value: 0.133 / Net I/σ(I): 7.6
Reflection shellResolution: 1.95→2.01 Å / Redundancy: 5.4 % / Rmerge(I) obs: 2.412 / Mean I/σ(I) obs: 7.6 / Num. unique obs: 6903 / CC1/2: 0.432 / Rpim(I) all: 1.676 / Rsym value: 2.412 / % possible all: 99.9

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Processing

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

4dip


Resolution: 1.959→88.712 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 30.17
RfactorNum. reflection% reflectionSelection details
Rfree0.2409 13718 5.04 %random
Rwork0.1974 ---
obs0.1996 139178 98.59 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.959→88.712 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms12886 0 548 608 14042
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01113904
X-RAY DIFFRACTIONf_angle_d1.0318951
X-RAY DIFFRACTIONf_dihedral_angle_d15.4838129
X-RAY DIFFRACTIONf_chiral_restr0.0551970
X-RAY DIFFRACTIONf_plane_restr0.0062426
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.959-1.98120.4064520.37348654X-RAY DIFFRACTION98
1.9812-2.00460.4124560.34818546X-RAY DIFFRACTION99
2.0046-2.0290.3454590.33348617X-RAY DIFFRACTION99
2.029-2.05470.33684720.32328667X-RAY DIFFRACTION98
2.0547-2.08170.33945200.3288478X-RAY DIFFRACTION98
2.0817-2.11020.3454820.31318584X-RAY DIFFRACTION99
2.1102-2.14040.33644940.30118569X-RAY DIFFRACTION99
2.1404-2.17230.34084520.2978574X-RAY DIFFRACTION98
2.1723-2.20630.29474130.27688706X-RAY DIFFRACTION98
2.2063-2.24250.33114850.27768485X-RAY DIFFRACTION98
2.2425-2.28110.30713930.27268718X-RAY DIFFRACTION98
2.2811-2.32260.28194880.2448600X-RAY DIFFRACTION99
2.3226-2.36730.28574570.23938666X-RAY DIFFRACTION99
2.3673-2.41560.29814520.23898596X-RAY DIFFRACTION99
2.4156-2.46820.31344820.23898640X-RAY DIFFRACTION99
2.4682-2.52560.26844530.22528614X-RAY DIFFRACTION99
2.5256-2.58870.26134480.21098611X-RAY DIFFRACTION98
2.5887-2.65870.27184990.20258492X-RAY DIFFRACTION98
2.6587-2.7370.23974640.20568480X-RAY DIFFRACTION98
2.737-2.82530.24094300.20358695X-RAY DIFFRACTION99
2.8253-2.92630.23564870.20248573X-RAY DIFFRACTION99
2.9263-3.04350.28513860.19968688X-RAY DIFFRACTION99
3.0435-3.1820.26354320.19468705X-RAY DIFFRACTION99
3.182-3.34980.2484590.18898597X-RAY DIFFRACTION99
3.3498-3.55960.22314750.1768557X-RAY DIFFRACTION98
3.5596-3.83450.21334430.15928629X-RAY DIFFRACTION99
3.8345-4.22040.16274790.13528714X-RAY DIFFRACTION99
4.2204-4.8310.17344290.12778663X-RAY DIFFRACTION99
4.831-6.08640.20554720.1448657X-RAY DIFFRACTION99
6.0864-88.80340.1734050.17778677X-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)
11.09590.2267-0.67272.2855-0.63382.35590.30930.47580.38970.06320.19210.4262-0.801-0.7961-0.31090.4880.25450.17750.59320.27150.465664.195530.8927-185.5708
21.1824-0.2527-0.45921.7426-0.78573.1170.054-0.05250.06220.35310.09590.0539-0.1698-0.1243-0.13130.2198-0.067-0.00150.19790.01520.259774.29287.7711-157.8667
30.71760.05680.29022.51330.02381.97010.1307-0.2649-0.27840.1613-0.00570.22360.7702-0.1912-0.07030.5576-0.0253-0.06850.33640.09960.362693.0467-34.8927-195.7255
40.92710.3080.39230.9609-0.00133.0069-0.02440.017-0.0545-0.1240.0802-0.0605-0.0760.2022-0.05580.23350.052-0.00950.1676-0.01310.2429103.4811-11.4044-223.1388
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND RESID 68:480 )A68 - 480
2X-RAY DIFFRACTION2( CHAIN B AND RESID 67:480 )B67 - 480
3X-RAY DIFFRACTION3( CHAIN C AND RESID 68:480 )C68 - 480
4X-RAY DIFFRACTION4( CHAIN D AND RESID 68:480 )D68 - 480

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