› 5vp1

X-ray diffraction
1.86Å resolution

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

Released:
DOI: 10.2210/pdb5vp1/pdb
PDB entry 5vp1 coloured by chain, front view.
PDB entry 5vp1 coloured by chain, side view.
PDB entry 5vp1 coloured by chain, top view.
Source organism: Homo sapiens
Primary publication:
Discovery of a Novel Series of Pyrazolo[1,5-a]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from 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), for the Treatment of Cognitive Disorders.
Mikami S, Kawasaki M, Ikeda S, Negoro N, Nakamura S, Nomura I, Ashizawa T, Kokubo H, Hoffman ID, Zou H, Oki H, Uchiyama N, Hiura Y, Miyamoto M, Itou Y, Nakashima M, Iwashita H, Taniguchi T
Chem Pharm Bull (Tokyo) 65 1058-1077 (2017)
PMID: 29093293

Function and Biology Details

Reaction catalysed: 
Nucleoside 3',5'-cyclic phosphate + H(2)O = nucleoside 5'-phosphate
Biochemical function:
Biological process:
Cellular component:
  • not assigned
Sequence domains:

Structure analysis Details

Assembly composition:
homo dimer (preferred)
Assembly name:
PDBe Complex ID:
PDB-CPX-126261 (preferred)
Entry contents:
1 distinct polypeptide molecule
Macromolecule:
cGMP-dependent 3',5'-cyclic phosphodiesterase Chains: A, B, C
Molecule details ›
Chains: A, B, C
Length: 345 amino acids
Theoretical weight: 40.23 KDa
Source organism: Homo sapiens
Expression system: Baculovirus expression vector pFastBac1-HM
UniProt:
  • Canonical: O00408 (Residues: 578-919; Coverage: 36%)
Gene name: PDE2A
Sequence domains: 3'5'-cyclic nucleotide phosphodiesterase
Structure domains: 3'5'-cyclic nucleotide phosphodiesterase, catalytic domain

Ligands and Environments

3 bound ligands:
Ligand ZN 3 x ZN
Ligand MG 4 x MG
Ligand 9GA 3 x 9GA
No modified residues

Experiments and Validation Details

Entry percentile scores
X-ray source: ALS BEAMLINE 5.0.2
Spacegroup: C2
Unit cell:
a: 165.129Å b: 72.712Å c: 90.061Å
α: 90° β: 109.15° γ: 90°
R-values:
R R work R free
0.225 0.224 0.243
Expression system: Baculovirus expression vector pFastBac1-HM

Quick links

Citations

1 review citation

Therapeutic targeting of 3',5'-cyclic nucleotide phosphodiesterases: inhibition and beyond.
Baillie et al. (2019)
4 other articles

1 mention without citation

Virus-Induced Cancers of the Skin and Mucosa: Are We Dealing with "Smoking Guns" or "Smoke and Mirrors" in the Operating Theatre?
Goon et al. (2017)