6NHF

Structure of human endothelial nitric oxide synthase heme domain in complex with (S)-6-(2,3-difluoro-5-(2-(1-methylazetidin-2-yl)ethyl)phenethyl)-4-methylpyridin-2-amine

External Resource: Annotation

Domain Annotation: SCOP/SCOPe Classification
Domain Annotation: SCOP2 Classification
Domain Annotation: ECOD Classification
Domain Annotation: CATH
Protein Family Annotation
Gene Ontology: Gene Product Annotation
InterPro: Protein Family Classification
Pharos: Disease Associations

Domain Annotation: SCOP/SCOPe Classification SCOP-e Database Homepage

Chains	Domain Info	Class	Fold	Superfamily	Family	Domain	Species	Provenance Source (Version)
C	d6nhfc_	Alpha and beta proteins (a+b)	Nitric oxide (NO) synthase oxygenase domain	Nitric oxide (NO) synthase oxygenase domain	Nitric oxide (NO) synthase oxygenase domain	automated matches	Human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
A	d6nhfa_	Alpha and beta proteins (a+b)	Nitric oxide (NO) synthase oxygenase domain	Nitric oxide (NO) synthase oxygenase domain	Nitric oxide (NO) synthase oxygenase domain	automated matches	Human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
B	d6nhfb_	Alpha and beta proteins (a+b)	Nitric oxide (NO) synthase oxygenase domain	Nitric oxide (NO) synthase oxygenase domain	Nitric oxide (NO) synthase oxygenase domain	automated matches	Human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
D	d6nhfd_	Alpha and beta proteins (a+b)	Nitric oxide (NO) synthase oxygenase domain	Nitric oxide (NO) synthase oxygenase domain	Nitric oxide (NO) synthase oxygenase domain	automated matches	Human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)

Domain Annotation: SCOP2 Classification SCOP2 Database Homepage

Chains	Type	Family Name	Domain Identifier	Family Identifier	Provenance Source (Version)
C	SCOP2B Superfamily	Nitric oxide (NO) synthase oxygenase domain	8079785	3001407	SCOP2B (2022-06-29)
A	SCOP2B Superfamily	Nitric oxide (NO) synthase oxygenase domain	8079785	3001407	SCOP2B (2022-06-29)
B	SCOP2B Superfamily	Nitric oxide (NO) synthase oxygenase domain	8079785	3001407	SCOP2B (2022-06-29)
D	SCOP2B Superfamily	Nitric oxide (NO) synthase oxygenase domain	8079785	3001407	SCOP2B (2022-06-29)

Domain Annotation: ECOD Classification ECOD Database Homepage

Chains	Family Name	Domain Identifier	Architecture	Possible Homology	Homology	Topology	Family	Provenance Source (Version)
C	NO_synthase	e6nhfC1	A: a+b complex topology	X: Nitric oxide (NO) synthase oxygenase domain (From Topology)	H: Nitric oxide (NO) synthase oxygenase domain (From Topology)	T: Nitric oxide (NO) synthase oxygenase domain	F: NO_synthase	ECOD (1.6)
A	NO_synthase	e6nhfA1	A: a+b complex topology	X: Nitric oxide (NO) synthase oxygenase domain (From Topology)	H: Nitric oxide (NO) synthase oxygenase domain (From Topology)	T: Nitric oxide (NO) synthase oxygenase domain	F: NO_synthase	ECOD (1.6)
B	NO_synthase	e6nhfB1	A: a+b complex topology	X: Nitric oxide (NO) synthase oxygenase domain (From Topology)	H: Nitric oxide (NO) synthase oxygenase domain (From Topology)	T: Nitric oxide (NO) synthase oxygenase domain	F: NO_synthase	ECOD (1.6)
D	NO_synthase	e6nhfD1	A: a+b complex topology	X: Nitric oxide (NO) synthase oxygenase domain (From Topology)	H: Nitric oxide (NO) synthase oxygenase domain (From Topology)	T: Nitric oxide (NO) synthase oxygenase domain	F: NO_synthase	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
C	3.90.340.10	Alpha Beta	Alpha-Beta Complex	Nitric Oxide Synthase	Chain A, domain 1	CATH (4.3.0)
C	3.90.440.10	Alpha Beta	Alpha-Beta Complex	Nitric Oxide Synthase	Heme Domain	CATH (4.3.0)
C	3.90.1230.10	Alpha Beta	Alpha-Beta Complex	Bovine Endothelial Nitric Oxide Synthase Heme Domain	Chain: A,domain 3	CATH (4.3.0)
A	3.90.340.10	Alpha Beta	Alpha-Beta Complex	Nitric Oxide Synthase	Chain A, domain 1	CATH (4.3.0)
A	3.90.440.10	Alpha Beta	Alpha-Beta Complex	Nitric Oxide Synthase	Heme Domain	CATH (4.3.0)
A	3.90.1230.10	Alpha Beta	Alpha-Beta Complex	Bovine Endothelial Nitric Oxide Synthase Heme Domain	Chain: A,domain 3	CATH (4.3.0)
B	3.90.340.10	Alpha Beta	Alpha-Beta Complex	Nitric Oxide Synthase	Chain A, domain 1	CATH (4.3.0)
B	3.90.440.10	Alpha Beta	Alpha-Beta Complex	Nitric Oxide Synthase	Heme Domain	CATH (4.3.0)
B	3.90.1230.10	Alpha Beta	Alpha-Beta Complex	Bovine Endothelial Nitric Oxide Synthase Heme Domain	Chain: A,domain 3	CATH (4.3.0)
D	3.90.340.10	Alpha Beta	Alpha-Beta Complex	Nitric Oxide Synthase	Chain A, domain 1	CATH (4.3.0)
D	3.90.440.10	Alpha Beta	Alpha-Beta Complex	Nitric Oxide Synthase	Heme Domain	CATH (4.3.0)
D	3.90.1230.10	Alpha Beta	Alpha-Beta Complex	Bovine Endothelial Nitric Oxide Synthase Heme Domain	Chain: A,domain 3	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
A, B, C, D	PF02898	Nitric oxide synthase, oxygenase domain (NO_synthase)	Nitric oxide synthase, oxygenase domain	-	Domain

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A, B, C, D	Endothelial nitric oxide synthase splice variant eNOS13A	binding nucleotide binding FMN binding nucleoside phosphate binding ion binding organic cyclic compound binding anion binding heterocyclic compound binding carbohydrate derivative binding ribonucleotide binding small molecule binding flavin adenine dinucleotide binding cation binding organic acid binding binding nucleotide binding FMN binding nucleoside phosphate binding ion binding organic cyclic compound binding anion binding heterocyclic compound binding carbohydrate derivative binding ribonucleotide binding small molecule binding flavin adenine dinucleotide binding cation binding organic acid binding amino acid binding carboxylic acid binding arginine binding transition metal ion binding cadmium ion binding metal ion binding oxidoreductase activity monooxygenase activity oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen nitric-oxide synthase activity oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen catalytic activity protein binding calmodulin binding cytoskeletal protein binding actin monomer binding actin binding tetrahydrobiopterin binding scaffold protein binding purine nucleotide binding adenyl nucleotide binding NADP binding tetrapyrrole binding heme binding	multicellular organismal process system process circulatory system process regulation of blood pressure biological regulation regulation of biological quality blood circulation developmental process heart development cardiac chamber morphogenesis animal organ development heart morphogenesis ventricular septum development circulatory system development multicellular organismal process system process circulatory system process regulation of blood pressure biological regulation regulation of biological quality blood circulation developmental process heart development cardiac chamber morphogenesis animal organ development heart morphogenesis ventricular septum development circulatory system development multicellular organism development anatomical structure morphogenesis cardiac septum development cardiac septum morphogenesis ventricular septum morphogenesis cardiac chamber development anatomical structure development animal organ morphogenesis cardiac ventricle development system development multicellular organismal-level homeostasis homeostatic process homeostasis of number of cells within a tissue anatomical structure homeostasis tissue homeostasis homeostasis of number of cells regulation of cellular process cellular biosynthetic process positive regulation of biological process positive regulation of cellular metabolic process positive regulation of macromolecule biosynthetic process positive regulation of metabolic process positive regulation of biosynthetic process positive regulation of macromolecule metabolic process positive regulation of cellular process regulation of biosynthetic process regulation of biological process cellular metabolic process regulation of cellular metabolic process regulation of macromolecule metabolic process gene expression macromolecule biosynthetic process regulation of cellular biosynthetic process regulation of gene expression biosynthetic process positive regulation of gene expression regulation of macromolecule biosynthetic process metabolic process cellular process macromolecule metabolic process regulation of metabolic process positive regulation of cellular biosynthetic process heart process regulation of heart contraction regulation of system process regulation of blood circulation regulation of multicellular organismal process regulation of the force of heart contraction by chemical signal heart contraction regulation of the force of heart contraction cellular response to stimulus extrinsic apoptotic signaling pathway via death domain receptors response to stimulus signaling negative regulation of signaling negative regulation of biological process regulation of signal transduction regulation of programmed cell death extrinsic apoptotic signaling pathway negative regulation of cell communication cell communication negative regulation of extrinsic apoptotic signaling pathway negative regulation of apoptotic signaling pathway negative regulation of cellular process signal transduction regulation of signaling cell surface receptor signaling pathway negative regulation of response to stimulus negative regulation of programmed cell death regulation of apoptotic process negative regulation of extrinsic apoptotic signaling pathway via death domain receptors cell death negative regulation of signal transduction regulation of extrinsic apoptotic signaling pathway apoptotic signaling pathway negative regulation of apoptotic process regulation of response to stimulus regulation of extrinsic apoptotic signaling pathway via death domain receptors regulation of cell communication apoptotic process programmed cell death regulation of apoptotic signaling pathway endothelial cell migration cell migration cell motility catabolic process oxoacid metabolic process glutamine family amino acid catabolic process amino acid metabolic process arginine catabolic process organic acid metabolic process organic acid catabolic process alpha-amino acid metabolic process glutamine family amino acid metabolic process cellular catabolic process arginine metabolic process carboxylic acid catabolic process small molecule metabolic process amino acid catabolic process carboxylic acid metabolic process L-amino acid catabolic process primary metabolic process L-amino acid metabolic process proteinogenic amino acid metabolic process alpha-amino acid catabolic process proteinogenic amino acid catabolic process small molecule catabolic process embryo development ending in birth or egg hatching chordate embryonic development embryo development in utero embryonic development regulation of localization regulation of calcium ion transport transport regulation of transport negative regulation of monoatomic ion transport regulation of monoatomic ion transport negative regulation of transport establishment of localization calcium ion transport metal ion transport negative regulation of calcium ion transport localization monoatomic ion transport monoatomic cation transport regulation of metal ion transport ovulation cycle process ovulation sexual reproduction reproductive process sex differentiation development of primary female sexual characteristics female gamete generation developmental process involved in reproduction gamete generation ovulation from ovarian follicle ovulation cycle development of primary sexual characteristics reproductive structure development rhythmic process gonad development reproductive system development female gonad development multicellular organismal reproductive process female sex differentiation cell redox homeostasis cellular homeostasis response to stress response to heat response to abiotic stimulus response to temperature stimulus response to hormone response to endogenous stimulus response to chemical response to fluid shear stress regulation of muscle adaptation negative regulation of muscle adaptation muscle hyperplasia muscle system process regulation of muscle system process muscle adaptation regulation of muscle hyperplasia negative regulation of muscle hyperplasia negative regulation of multicellular organismal process regulation of body fluid levels regulation of response to external stimulus regulation of cell activation negative regulation of platelet activation regulation of response to wounding regulation of coagulation regulation of response to stress coagulation response to wounding regulation of hemostasis wound healing negative regulation of wound healing regulation of blood coagulation negative regulation of blood coagulation hemostasis cell activation response to external stimulus negative regulation of response to wounding blood coagulation negative regulation of cell activation negative regulation of hemostasis regulation of platelet activation negative regulation of coagulation negative regulation of response to external stimulus regulation of wound healing platelet activation negative regulation of potassium ion transport regulation of potassium ion transport potassium ion transport nervous system process regulation of nervous system process blood vessel morphogenesis tube development angiogenesis vasculature development tube morphogenesis anatomical structure formation involved in morphogenesis blood vessel development nitric oxide mediated signal transduction intracellular signal transduction intracellular signaling cassette cellular response to oxidative stress detoxification reactive oxygen species metabolic process cellular response to chemical stress response to superoxide cellular oxidant detoxification cellular response to oxygen radical cellular response to reactive oxygen species cellular response to stress cellular detoxification response to oxygen-containing compound cellular response to oxygen-containing compound response to reactive oxygen species response to toxic substance removal of superoxide radicals superoxide metabolic process response to oxidative stress cellular response to chemical stimulus cellular response to superoxide cellular response to toxic substance response to oxygen radical regulation of systemic arterial blood pressure by endothelin regulation of systemic arterial blood pressure by hormone regulation of systemic arterial blood pressure mediated by a chemical signal regulation of systemic arterial blood pressure endocrine process biological process involved in interspecies interaction between organisms response to lipid cellular response to lipopolysaccharide response to biotic stimulus lipopolysaccharide-mediated signaling pathway cellular response to biotic stimulus response to bacterium response to external biotic stimulus response to other organism cellular response to molecule of bacterial origin response to lipopolysaccharide cellular response to lipid response to molecule of bacterial origin respiratory tube development lung development respiratory system development negative regulation of cell population proliferation cell population proliferation regulation of smooth muscle cell proliferation smooth muscle cell proliferation negative regulation of smooth muscle cell proliferation regulation of cell population proliferation muscle cell proliferation cellular localization establishment of localization in cell regulation of tube diameter regulation of tube size vascular process in circulatory system blood vessel diameter maintenance vasodilation regulation of anatomical structure size heart valve development aortic valve development heart valve morphogenesis semi-lunar valve development aortic valve morphogenesis positive regulation of locomotion regulation of cell motility regulation of blood vessel endothelial cell migration positive regulation of cell migration positive regulation of blood vessel endothelial cell migration regulation of locomotion positive regulation of endothelial cell migration positive regulation of cell motility regulation of cell migration blood vessel endothelial cell migration regulation of endothelial cell migration locomotion mesenchyme morphogenesis endocardial cushion morphogenesis mesenchyme development tissue development tissue morphogenesis endocardial cushion development blood vessel remodeling tissue remodeling pulmonary valve morphogenesis pulmonary valve development regulation of developmental process regulation of vasculature development positive regulation of developmental process regulation of anatomical structure morphogenesis regulation of multicellular organismal development positive regulation of angiogenesis positive regulation of vasculature development regulation of angiogenesis positive regulation of multicellular organismal process negative regulation of developmental process negative regulation of biomineral tissue development regulation of biomineral tissue development biomineral tissue development positive regulation of cell communication positive regulation of signal transduction positive regulation of response to stimulus Notch signaling pathway regulation of Notch signaling pathway positive regulation of Notch signaling pathway positive regulation of signaling cellular component organization organelle organization cellular component organization or biogenesis mitochondrion organization regulation of sodium ion transport sodium ion transport smooth muscle hyperplasia smooth muscle adaptation negative regulation of blood pressure nitric oxide metabolic process nitric oxide biosynthetic process reactive nitrogen species metabolic process regulation of catalytic activity nucleotide biosynthetic process positive regulation of phosphate metabolic process positive regulation of nucleotide biosynthetic process regulation of nucleotide biosynthetic process regulation of primary metabolic process nucleobase-containing compound metabolic process regulation of lyase activity positive regulation of purine nucleotide biosynthetic process regulation of small molecule metabolic process regulation of phosphate metabolic process regulation of nucleotide metabolic process phosphate-containing compound metabolic process regulation of nucleobase-containing compound metabolic process phosphorus metabolic process positive regulation of lyase activity nucleoside phosphate metabolic process positive regulation of nucleobase-containing compound metabolic process positive regulation of phosphorus metabolic process positive regulation of guanylate cyclase activity nucleotide metabolic process regulation of purine nucleotide metabolic process regulation of molecular function organophosphate biosynthetic process nucleoside phosphate biosynthetic process regulation of phosphorus metabolic process purine nucleotide biosynthetic process positive regulation of nucleotide metabolic process positive regulation of molecular function regulation of guanylate cyclase activity purine nucleotide metabolic process nucleobase-containing small molecule metabolic process purine-containing compound biosynthetic process regulation of cyclase activity regulation of purine nucleotide biosynthetic process positive regulation of cyclase activity positive regulation of catalytic activity nucleobase-containing compound biosynthetic process purine-containing compound metabolic process positive regulation of purine nucleotide metabolic process organophosphate metabolic process positive regulation of small molecule metabolic process	intracellular anatomical structure cytoplasm cellular anatomical entity cytosol membrane-bounded organelle membrane intracellular vesicle intracellular membrane-bounded organelle intracellular organelle cytoplasmic vesicle membrane bounding membrane of organelle cytoplasmic vesicle vesicle membrane organelle intracellular anatomical structure cytoplasm cellular anatomical entity cytosol membrane-bounded organelle membrane intracellular vesicle intracellular membrane-bounded organelle intracellular organelle cytoplasmic vesicle membrane bounding membrane of organelle cytoplasmic vesicle vesicle membrane organelle endocytic vesicle membrane vesicle organelle membrane endocytic vesicle Golgi apparatus endomembrane system cytoskeleton intracellular non-membrane-bounded organelle non-membrane-bounded organelle Golgi membrane membrane microdomain cell periphery membrane raft plasma membrane raft plasma membrane plasma membrane region caveola nucleus

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A, B, C, D	IPR001709	Flavoprotein pyridine nucleotide cytochrome reductase	Domain
A, B, C, D	IPR001433	Oxidoreductase FAD/NAD(P)-binding	Domain
A, B, C, D	IPR001094	Flavodoxin-like	Domain
A, B, C, D	IPR004030	Nitric oxide synthase, N-terminal	Domain
A, B, C, D	IPR023173	NADPH-cytochrome p450 reductase, FAD-binding, alpha-helical domain superfamily	Homologous Superfamily
A, B, C, D	IPR008254	Flavodoxin/nitric oxide synthase	Domain
A, B, C, D	IPR039261	Ferredoxin-NADP reductase (FNR), nucleotide-binding domain	Homologous Superfamily
A, B, C, D	IPR017927	FAD-binding domain, ferredoxin reductase-type	Domain
A, B, C, D	IPR036119	Nitric oxide synthase, N-terminal domain superfamily	Homologous Superfamily
A, B, C, D	IPR044944	Nitric oxide synthase, domain 3 superfamily	Homologous Superfamily
A, B, C, D	IPR044943	Nitric oxide synthase, domain 1 superfamily	Homologous Superfamily
A, B, C, D	IPR003097	Sulfite reductase [NADPH] flavoprotein alpha-component-like, FAD-binding	Domain
A, B, C, D	IPR017938	Riboflavin synthase-like beta-barrel	Homologous Superfamily
A, B, C, D	IPR044940	Nitric oxide synthase, domain 2 superfamily	Homologous Superfamily
A, B, C, D	IPR029039	Flavoprotein-like superfamily	Homologous Superfamily
A, B, C, D	IPR050607	Nitric Oxide Synthase (NOS)	Family
A, B, C, D	IPR012144	Nitric-oxide synthase, eukaryote	Family

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
A, B, C, D	Pharos: P29474	hypertensive disorder atrial fibrillation metabolic syndrome X cleft palate atherosclerosis erectile dysfunction coronary artery disease hyperglycemia myocardial infarction type 2 diabetes mellitus portal hypertension Alzheimer disease Sepsis diabetic peripheral angiopathy cancer hypertensive disorder atrial fibrillation metabolic syndrome X cleft palate atherosclerosis erectile dysfunction coronary artery disease hyperglycemia myocardial infarction type 2 diabetes mellitus portal hypertension Alzheimer disease Sepsis diabetic peripheral angiopathy cancer tubular adenocarcinoma cardiovascular disease essential hypertension uremia ventricular tachycardia intestinal perforation gastric ulcer male infertility pulmonary edema renovascular hypertension hyperinsulinism breast carcinoma hypertension, pregnancy-induced cerebral infarction ureteral obstruction cerebrovascular disorder placental abruption vestibular disease prostate cancer granular cell carcinoma pulmonary hypertension arteriosclerosis disorder esophageal cancer perinatal necrotizing enterocolitis adenocarcinoma preeclampsia congestive heart failure coronary vasospasm atypical teratoid rhabdoid tumor medulloblastoma breast cancer myocardial ischemia neoplasm of esophagus obesity disorder extrahepatic cholestasis familial hyperlipidemia ischemic disease Alzheimer disease type 1 primary biliary cholangitis heart disease cribriform carcinoma depressive disorder HELLP syndrome hereditary diffuse gastric adenocarcinoma benign neoplasm diabetic kidney disease thrombotic disease type 1 diabetes mellitus essential hypertension, genetic chronic obstructive pulmonary disease alopecia areata kidney disease gastric cancer congenital diaphragmatic hernia heart failure cribriform carcinoma of breast maturity-onset diabetes of the young bipolar disorder hyperlipidemia necrotizing enterocolitis acute kidney failure inborn carbohydrate metabolic disorder interstitial cystitis familial atrial fibrillation allergic rhinitis ischemia reperfusion injury cleft lip fetal growth restriction gastric neoplasm malignant glioma

RCSB PDB Core Operations are funded by the U.S. National Science Foundation (DBI-2321666), the US Department of Energy (DE-SC0019749), and the National Cancer Institute, National Institute of Allergy and Infectious Diseases, and National Institute of General Medical Sciences of the National Institutes of Health under grant R01GM157729.