4z2b
The structure of human PDE12 residues 161-609 in complex with GSK3036342A
Structural highlights
FunctionPDE12_HUMAN Enzyme that cleaves 2',5'-phosphodiester bond linking adenosines of the 5'-triphosphorylated oligoadenylates, triphosphorylated oligoadenylates referred as 2-5A modulates the 2-5A system. This enzyme degraded triphosphorylated 2-5A to produce AMP and ATP. Also cleaves 3',5'-phosphodiester bond of oligoadenylates. Plays a role as a negative regulator of the The 2-5A system that is one of the major pathways for antiviral and antitumor functions induced by interferons (IFNs). Suppression of this enzyme induces reduction of viral replication in Hela cells, thus counteracting the antiviral pathway probably by inhibiting the 2-5A system.[1] [2] [3] [4] Publication Abstract from PubMed2',5'-oligoadenylate synthetase (OAS) enzymes and RNase-L constitute a major effector arm of interferon (IFN) mediated antiviral defense. OAS produces a unique oligonucleotide second messenger, 2',5'-oligoadenylate (2-5A), that binds and activates RNase-L. This pathway is down regulated by viral and host encoded enzymes that degrade 2-5A. Phosphodiesterase 12 (PDE12) was the first cellular 2-5A degrading enzyme to be purified and described at a molecular level. Inhibition of PDE12 may up regulate the OAS/RNase-L pathway in response to viral infection resulting in increased resistance to a variety of viral pathogens. We generated a PDE12 null cell-line, HeLaDeltaPDE12, using transcription activator-like effector nuclease (TALEN) mediated gene inactivation. This cell line has increased 2-5A levels in response to IFN and polyinosinic-polycytidylic acid (poly IC), a double-stranded RNA mimic compared to the parental cell line. Moreover, HeLaDeltaPDE12 cells were resistant to viral pathogens including encephalomyocarditis virus (EMCV), human rhinovirus (HRV), and respiratory syncytial virus (RSV). Based on these results, we used DNA-encoded chemical library screening to identify starting points for inhibitor lead optimization. Compounds derived from this effort raise 2-5A levels and exhibit antiviral activity comparable to the effects observed with PDE12 gene inactivation. The crystal structure of PDE12 complexed with an inhibitor was solved providing insights into the structure activity relationships of inhibitor potency and selectivity. The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors.,Wood ER, Bledsoe R, Chai J, Daka P, Deng H, Ding Y, Harris-Gurley S, Kryn LH, Nartey E, Nichols J, Nolte RT, Prabhu N, Rise C, Sheahan T, Shotwell JB, Smith D, Tai V, Taylor JD, Tomberlin G, Wang L, Wisely B, You S, Xia B, Dickson H J Biol Chem. 2015 Jun 8. pii: jbc.M115.653113. PMID:26055709[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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