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- PDB-6nh7: Structure of human endothelial nitric oxide synthase heme domain ... -

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Basic information

Entry
Database: PDB / ID: 6nh7
TitleStructure of human endothelial nitric oxide synthase heme domain in complex with 6-(3-(3-(dimethylamino)propyl)-2,5,6-trifluorophenethyl)-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 / 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 / nitric oxide mediated signal transduction / negative regulation of platelet activation / actin monomer binding / 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 / response to hormone / eNOS activation / nitric oxide metabolic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / negative regulation of blood pressure / nitric oxide biosynthetic process / homeostasis of number of cells within a tissue / removal of superoxide radicals / cell redox homeostasis / lipopolysaccharide-mediated signaling pathway / blood vessel diameter maintenance / VEGFR2 mediated vascular permeability / mitochondrion organization / negative regulation of smooth muscle cell proliferation / lung development / establishment of localization in cell / potassium ion transport / regulation of blood pressure / caveola / positive regulation of angiogenesis / calcium ion transport / endocytic vesicle membrane / vasodilation / FMN binding / flavin adenine dinucleotide binding / NADP binding / response to heat / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / scaffold protein binding / angiogenesis / response to lipopolysaccharide / in utero embryonic development / cytoskeleton / Extra-nuclear estrogen signaling / calmodulin binding / Golgi membrane / negative regulation of cell population proliferation / heme binding / positive regulation of gene expression / Golgi apparatus / metal ion binding / 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
GADOLINIUM ATOM / PROTOPORPHYRIN IX CONTAINING FE / Chem-KMM / Nitric oxide synthase 3 / Nitric oxide synthase 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.9 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.ptnr2_symmetry / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,48920
Polymers98,6922
Non-polymers4,79818
Water4,882271
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10120 Å2
ΔGint-140 kcal/mol
Surface area34410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)55.959, 109.381, 153.470
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Endothelial nitric oxide synthase splice variant eNOS13A


Mass: 49345.770 Da / Num. of mol.: 2
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 , 6 types, 289 molecules

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


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-KMM / 6-(2-{3-[3-(dimethylamino)propyl]-2,5,6-trifluorophenyl}ethyl)-4-methylpyridin-2-amine


Mass: 351.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C19H24F3N3
#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.: 7 / Source method: obtained synthetically / Formula: C8H19NO5 / Comment: pH buffer*YM
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#6: Chemical
ChemComp-GD / GADOLINIUM ATOM


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


Mass: 18.015 Da / Num. of mol.: 271 / 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: 2.38 Å3/Da / Density % sol: 48.31 % / 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: Oct 14, 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: 1.9→77 Å / Num. obs: 75181 / % possible obs: 100 % / Observed criterion σ(I): -3 / Redundancy: 8.2 % / CC1/2: 0.998 / Rmerge(I) obs: 0.158 / Rpim(I) all: 0.082 / Rsym value: 0.158 / Net I/σ(I): 7.3
Reflection shellResolution: 1.9→1.96 Å / Redundancy: 8.1 % / Rmerge(I) obs: 3.008 / Mean I/σ(I) obs: 1 / Num. unique obs: 4415 / CC1/2: 0.518 / Rpim(I) all: 1.62 / Rsym value: 3.008 / % possible all: 99.8

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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: 1.9→76.735 Å / SU ML: 0.24 / Cross valid method: FREE R-VALUE / σ(F): 0.03 / Phase error: 34.26
RfactorNum. reflection% reflectionSelection details
Rfree0.2581 7133 4.98 %random
Rwork0.2101 ---
obs0.2125 75005 99.77 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.9→76.735 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6409 0 289 271 6969
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0086970
X-RAY DIFFRACTIONf_angle_d0.9859493
X-RAY DIFFRACTIONf_dihedral_angle_d15.4954068
X-RAY DIFFRACTIONf_chiral_restr0.054980
X-RAY DIFFRACTIONf_plane_restr0.0061217
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8999-1.92150.42452630.40394522X-RAY DIFFRACTION99
1.9215-1.94410.37842230.37524512X-RAY DIFFRACTION99
1.9441-1.96780.37822440.35764481X-RAY DIFFRACTION100
1.9678-1.99270.40182420.35474588X-RAY DIFFRACTION100
1.9927-2.01890.35482050.33624495X-RAY DIFFRACTION100
2.0189-2.04660.39392430.32664572X-RAY DIFFRACTION100
2.0466-2.07580.40372310.32014551X-RAY DIFFRACTION100
2.0758-2.10680.3771940.31774558X-RAY DIFFRACTION100
2.1068-2.13970.35982220.30264554X-RAY DIFFRACTION100
2.1397-2.17480.32282470.29134503X-RAY DIFFRACTION100
2.1748-2.21230.3292360.28954516X-RAY DIFFRACTION100
2.2123-2.25260.3542630.29534531X-RAY DIFFRACTION100
2.2526-2.29590.3142220.26554521X-RAY DIFFRACTION99
2.2959-2.34280.3162150.26274539X-RAY DIFFRACTION100
2.3428-2.39370.32482630.23994493X-RAY DIFFRACTION100
2.3937-2.44940.29142330.23584580X-RAY DIFFRACTION100
2.4494-2.51060.28132750.23364513X-RAY DIFFRACTION100
2.5106-2.57850.25352280.22534521X-RAY DIFFRACTION100
2.5785-2.65440.34332440.21454571X-RAY DIFFRACTION100
2.6544-2.74010.29442090.21984531X-RAY DIFFRACTION100
2.7401-2.8380.27812680.2184493X-RAY DIFFRACTION100
2.838-2.95170.27472510.21514581X-RAY DIFFRACTION100
2.9517-3.0860.24722360.20574526X-RAY DIFFRACTION100
3.086-3.24870.26442040.20484558X-RAY DIFFRACTION100
3.2487-3.45220.24472300.18854538X-RAY DIFFRACTION100
3.4522-3.71880.2262520.16994571X-RAY DIFFRACTION100
3.7188-4.0930.17852430.15074505X-RAY DIFFRACTION100
4.093-4.68520.17512550.13764532X-RAY DIFFRACTION100
4.6852-5.90250.19832620.1534489X-RAY DIFFRACTION100
5.9025-76.79760.2312300.18474560X-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)
10.7797-0.3792-0.06791.79940.25772.71260.20490.17170.1386-0.8452-0.1731-0.3698-0.31220.2656-0.02620.53460.07820.12260.31620.06850.3384-14.235822.376-33.9464
21.1967-0.4147-0.33622.4655-0.46862.43770.09210.0041-0.1157-0.2459-0.04670.04090.7445-0.0103-0.01790.3673-0.0053-0.13650.2666-0.0040.2429-23.7571-5.3247-9.8618
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)

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