4Z2B

The structure of human PDE12 residues 161-609 in complex with GSK3036342A

4Z2B の概要

• エントリーDOI: 10.2210/pdb4z2b/pdb
• 関連するPDBエントリー: 4Z0V
• 分子名称: 2',5'-phosphodiesterase 12, SULFATE ION, 1,2-ETHANEDIOL, ... (7 entities in total)
• 機能のキーワード: pde12 2'-5'a eep nuclease inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Mitochondrion matrix : Q6L8Q7
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 51995.86

構造登録者

Nolte, R.T.,Wisely, B.,Wang, L.,Wood, E.R. (登録日: 2015-03-29, 公開日: 2015-06-17, 最終更新日: 2023-09-27)

主引用文献

Wood, E.R.,Bledsoe, R.,Chai, J.,Daka, P.,Deng, H.,Ding, Y.,Harris-Gurley, S.,Kryn, L.H.,Nartey, E.,Nichols, J.,Nolte, R.T.,Prabhu, N.,Rise, C.,Sheahan, T.,Shotwell, J.B.,Smith, D.,Tai, V.,Taylor, J.D.,Tomberlin, G.,Wang, L.,Wisely, B.,You, S.,Xia, B.,Dickson, H.
The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors.
J.Biol.Chem., 290:19681-19696, 2015

PubMed Abstract: 2',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 virus- 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, HeLaΔPDE12, using transcription activator-like effector nuclease-mediated gene inactivation. This cell line has increased 2-5A levels in response to IFN and poly(I-C), a double-stranded RNA mimic compared with the parental cell line. Moreover, HeLaΔPDE12 cells were resistant to viral pathogens, including encephalomyocarditis virus, human rhinovirus, and respiratory syncytial virus. 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 with 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.

PubMed: 26055709
DOI: 10.1074/jbc.M115.653113

実験手法

X-RAY DIFFRACTION (1.8 Å)