5VP1

Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders

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)
A	d5vp1a_	All alpha proteins	HD-domain/PDEase-like	HD-domain/PDEase-like	automated matches	automated matches	Human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
B	d5vp1b1	All alpha proteins	HD-domain/PDEase-like	HD-domain/PDEase-like	automated matches	automated matches	Human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
B	d5vp1b2	Artifacts	Tags	Tags	Tags	N-terminal Tags	Human (Homo sapiens ) [TaxId: 9606 ],	SCOPe (2.08)
C	d5vp1c_	All alpha proteins	HD-domain/PDEase-like	HD-domain/PDEase-like	automated matches	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)
A	SCOP2B Superfamily	HD-domain/PDEase-like	8067455	3000943	SCOP2B (2022-06-29)
B	SCOP2B Superfamily	HD-domain/PDEase-like	8067455	3000943	SCOP2B (2022-06-29)
C	SCOP2B Superfamily	HD-domain/PDEase-like	8067455	3000943	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)
A	PDEase_I	e5vp1A1	A: alpha complex topology	X: PDEase-like	H: HD-domain/PDEase-like (From Topology)	T: HD-domain/PDEase-like	F: PDEase_I	ECOD (1.6)
B	PDEase_I	e5vp1B1	A: alpha complex topology	X: PDEase-like	H: HD-domain/PDEase-like (From Topology)	T: HD-domain/PDEase-like	F: PDEase_I	ECOD (1.6)
C	PDEase_I	e5vp1C1	A: alpha complex topology	X: PDEase-like	H: HD-domain/PDEase-like (From Topology)	T: HD-domain/PDEase-like	F: PDEase_I	ECOD (1.6)

Domain Annotation: CATH CATH Database Homepage

Chain	Domain	Class	Architecture	Topology	Homology	Provenance Source (Version)
A	1.10.1300.10	Mainly Alpha	Orthogonal Bundle	Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b	3'5'-cyclic nucleotide phosphodiesterase, catalytic domain	CATH (4.3.0)
B	1.10.1300.10	Mainly Alpha	Orthogonal Bundle	Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b	3'5'-cyclic nucleotide phosphodiesterase, catalytic domain	CATH (4.3.0)
C	1.10.1300.10	Mainly Alpha	Orthogonal Bundle	Catalytic domain of cyclic nucleotide phosphodiesterase 4b2b	3'5'-cyclic nucleotide phosphodiesterase, catalytic domain	CATH (4.3.0)

Protein Family Annotation Pfam Database Homepage

Chains	Accession	Name	Description	Comments	Source
A, B, C	PF00233	3'5'-cyclic nucleotide phosphodiesterase (PDEase_I)	3'5'-cyclic nucleotide phosphodiesterase	-	Domain

Gene Ontology: Gene Product Annotation Gene Ontology Database Homepage

Chains	Polymer	Molecular Function	Biological Process	Cellular Component
A, B, C	cGMP-dependent 3',5'-cyclic phosphodiesterase	guanyl nucleotide binding binding cyclic nucleotide binding nucleotide binding guanyl ribonucleotide binding purine ribonucleotide binding nucleoside phosphate binding ion binding purine nucleotide binding organic cyclic compound binding anion binding heterocyclic compound binding carbohydrate derivative binding ribonucleotide binding guanyl nucleotide binding binding cyclic nucleotide binding nucleotide binding guanyl ribonucleotide binding purine ribonucleotide binding nucleoside phosphate binding ion binding purine nucleotide binding organic cyclic compound binding anion binding heterocyclic compound binding carbohydrate derivative binding ribonucleotide binding cGMP binding small molecule binding phosphoric ester hydrolase activity hydrolase activity, acting on ester bonds phosphoric diester hydrolase activity 3',5'-cyclic-nucleotide phosphodiesterase activity 3',5'-cyclic-AMP phosphodiesterase activity hydrolase activity cyclic-nucleotide phosphodiesterase activity catalytic activity identical protein binding protein binding cation binding magnesium ion binding metal ion binding cGMP-stimulated cyclic-nucleotide phosphodiesterase activity phosphate ion binding protein homodimerization activity protein dimerization activity adenyl ribonucleotide binding cAMP binding adenyl nucleotide binding TPR domain binding protein domain specific binding transition metal ion binding zinc ion binding 3',5'-cyclic-GMP phosphodiesterase activity	cellular response to stimulus response to organic substance response to stimulus response to cytokine response to macrophage colony-stimulating factor cellular response to macrophage colony-stimulating factor stimulus cellular response to chemical stimulus response to chemical cellular response to cytokine stimulus cellular process cellular response to organic substance regulation of defense response regulation of biological process regulation of response to external stimulus cellular response to stimulus response to organic substance response to stimulus response to cytokine response to macrophage colony-stimulating factor cellular response to macrophage colony-stimulating factor stimulus cellular response to chemical stimulus response to chemical cellular response to cytokine stimulus cellular process cellular response to organic substance regulation of defense response regulation of biological process regulation of response to external stimulus defense response biological regulation positive regulation of biological process response to external stimulus regulation of inflammatory response positive regulation of response to stimulus positive regulation of response to external stimulus positive regulation of inflammatory response regulation of response to stimulus regulation of response to stress response to stress positive regulation of defense response inflammatory response ribose phosphate metabolic process ribonucleotide catabolic process catabolic process carbohydrate derivative metabolic process organophosphate catabolic process nucleoside phosphate catabolic process cyclic nucleotide metabolic process nucleobase-containing compound metabolic process purine nucleotide metabolic process organic substance metabolic process ribonucleotide metabolic process nucleobase-containing small molecule metabolic process phosphate-containing compound metabolic process small molecule metabolic process purine ribonucleotide catabolic process phosphorus metabolic process nucleotide catabolic process nucleoside phosphate metabolic process organonitrogen compound catabolic process purine nucleotide catabolic process carbohydrate derivative catabolic process organonitrogen compound metabolic process cyclic purine nucleotide metabolic process cellular metabolic process primary metabolic process purine-containing compound catabolic process cyclic nucleotide catabolic process nucleotide metabolic process organic cyclic compound catabolic process purine-containing compound metabolic process nucleobase-containing compound catabolic process organic cyclic compound metabolic process cGMP metabolic process organophosphate metabolic process cGMP catabolic process metabolic process purine ribonucleotide metabolic process organic substance catabolic process regulation of cellular process cellular biosynthetic process positive regulation of cellular metabolic process positive regulation of macromolecule biosynthetic process positive regulation of metabolic process positive regulation of biosynthetic process organic substance biosynthetic process positive regulation of macromolecule metabolic process positive regulation of cellular process regulation of biosynthetic 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 macromolecule metabolic process regulation of metabolic process positive regulation of cellular biosynthetic process signaling negative regulation of signaling negative regulation of intracellular signal transduction negative regulation of biological process regulation of signal transduction intracellular signal transduction negative regulation of cell communication cell communication regulation of intracellular signal transduction intracellular signaling cassette negative regulation of cellular process signal transduction regulation of cGMP-mediated signaling regulation of signaling negative regulation of cGMP-mediated signaling negative regulation of response to stimulus cGMP-mediated signaling negative regulation of signal transduction regulation of cell communication developmental process multicellular organism development multicellular organismal process artery development anatomical structure development aorta development vasculature development blood vessel development system development circulatory system development negative regulation of vascular permeability regulation of vascular permeability system process circulatory system process vascular process in circulatory system regulation of biological quality blood circulation regulation of cellular component organization regulation of organelle organization cellular component organization organelle organization regulation of mitochondrion organization cellular component organization or biogenesis mitochondrion organization positive regulation of vascular permeability myeloid leukocyte differentiation cellular developmental process hemopoiesis cell development mononuclear cell differentiation myeloid cell differentiation cell differentiation monocyte differentiation leukocyte differentiation cellular response to xenobiotic stimulus response to xenobiotic stimulus cAMP-mediated signaling negative regulation of cAMP-mediated signaling regulation of cAMP-mediated signaling negative regulation of cellular metabolic process regulation of primary metabolic process negative regulation of RNA biosynthetic process DNA-templated transcription regulation of RNA metabolic process transcription by RNA polymerase II negative regulation of nucleobase-containing compound metabolic process regulation of nucleobase-containing compound metabolic process regulation of transcription by RNA polymerase II negative regulation of DNA-templated transcription negative regulation of transcription by RNA polymerase II negative regulation of metabolic process negative regulation of cellular biosynthetic process negative regulation of macromolecule biosynthetic process organic cyclic compound biosynthetic process regulation of DNA-templated transcription negative regulation of RNA metabolic process RNA metabolic process RNA biosynthetic process nucleic acid biosynthetic process regulation of RNA biosynthetic process negative regulation of macromolecule metabolic process nucleobase-containing compound biosynthetic process nucleic acid metabolic process negative regulation of biosynthetic process cellular response to nitrogen compound response to endogenous stimulus response to organonitrogen compound response to organophosphorus cellular response to organic cyclic compound cellular response to cGMP response to oxygen-containing compound response to nitrogen compound response to cGMP response to purine-containing compound cellular response to oxygen-containing compound cellular response to endogenous stimulus cellular response to organonitrogen compound response to organic cyclic compound heart development animal organ development ventricular septum development cardiac septum development cardiac chamber development cardiac ventricle development response to 2,3,7,8-tetrachlorodibenzodioxine cellular response to 2,3,7,8-tetrachlorodibenzodioxine cellular response to growth factor stimulus response to transforming growth factor beta cellular response to transforming growth factor beta stimulus response to growth factor response to cAMP cellular response to cAMP response to granulocyte macrophage colony-stimulating factor cellular response to granulocyte macrophage colony-stimulating factor stimulus heart valve development response to mechanical stimulus response to abiotic stimulus cellular response to mechanical stimulus cellular response to abiotic stimulus cellular response to external stimulus cellular response to environmental stimulus epithelium development endothelial cell differentiation endothelium development tissue development epithelial cell differentiation endothelial cell development epithelial cell development establishment of endothelial barrier adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway adenylate cyclase-modulating G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway	intracellular anatomical structure cytoplasm cellular anatomical entity cytosol cell periphery presynapse synapse cell junction membrane plasma membrane presynaptic membrane plasma membrane region synaptic membrane membrane-bounded organelle intracellular anatomical structure cytoplasm cellular anatomical entity cytosol cell periphery presynapse synapse cell junction membrane plasma membrane presynaptic membrane plasma membrane region synaptic membrane membrane-bounded organelle intracellular organelle Golgi apparatus organelle intracellular membrane-bounded organelle endomembrane system perinuclear region of cytoplasm mitochondrial membrane mitochondrion organelle outer membrane organelle envelope bounding membrane of organelle mitochondrial envelope mitochondrial outer membrane outer membrane organelle membrane organelle inner membrane mitochondrial inner membrane membrane-enclosed lumen mitochondrial matrix intracellular organelle lumen organelle lumen nucleus endoplasmic reticulum

InterPro: Protein Family Classification InterPro Database Homepage

Chains	Accession	Name	Type
A, B, C	IPR023174	3'5'-cyclic nucleotide phosphodiesterase, conserved site	Conserved Site
A, B, C	IPR029016	GAF-like domain superfamily	Homologous Superfamily
A, B, C	IPR036971	3'5'-cyclic nucleotide phosphodiesterase, catalytic domain superfamily	Homologous Superfamily
A, B, C	IPR003018	GAF domain	Domain
A, B, C	IPR003607	HD/PDEase domain	Domain
A, B, C	IPR002073	3'5'-cyclic nucleotide phosphodiesterase, catalytic domain	Domain
A, B, C	IPR023088	3'5'-cyclic nucleotide phosphodiesterase	Family

Pharos: Disease Associations Pharos Homepage Annotation

Chains	Drug Target	Associated Disease
A, B, C	Pharos: O00408	breast carcinoma breast cancer rheumatoid arthritis oligodendroglioma Pick disease Prevention of Cerebral Thrombosis tuberculosis astrocytic tumor invasive ductal breast carcinoma malignant ependymoma osteosarcoma pilocytic astrocytoma primitive neuroectodermal tumor atrial fibrillation ductal breast carcinoma in situ breast carcinoma breast cancer rheumatoid arthritis oligodendroglioma Pick disease Prevention of Cerebral Thrombosis tuberculosis astrocytic tumor invasive ductal breast carcinoma malignant ependymoma osteosarcoma pilocytic astrocytoma primitive neuroectodermal tumor atrial fibrillation ductal breast carcinoma in situ large cell medulloblastoma malignant glioma non-small cell lung carcinoma pancreatic intraductal papillary-mucinous neoplasm atypical teratoid rhabdoid tumor breast fibroadenoma glioblastoma lung adenocarcinoma medulloblastoma

RCSB PDB Core Operations are funded by the National Science Foundation (DBI-1832184), 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 R01GM133198.