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4z2b

From Proteopedia

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Current revision

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

Structural highlights

4z2b is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PDE12_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 PubMed

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 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.

References

↑ Kubota K, Nakahara K, Ohtsuka T, Yoshida S, Kawaguchi J, Fujita Y, Ozeki Y, Hara A, Yoshimura C, Furukawa H, Haruyama H, Ichikawa K, Yamashita M, Matsuoka T, Iijima Y. Identification of 2'-phosphodiesterase, which plays a role in the 2-5A system regulated by interferon. J Biol Chem. 2004 Sep 3;279(36):37832-41. Epub 2004 Jun 30. PMID:15231837 doi:http://dx.doi.org/10.1074/jbc.M400089200
↑ Poulsen JB, Andersen KR, Kjaer KH, Durand F, Faou P, Vestergaard AL, Talbo GH, Hoogenraad N, Brodersen DE, Justesen J, Martensen PM. Human 2'-phosphodiesterase localizes to the mitochondrial matrix with a putative function in mitochondrial RNA turnover. Nucleic Acids Res. 2011 May;39(9):3754-70. doi: 10.1093/nar/gkq1282. Epub 2011, Jan 17. PMID:21245038 doi:http://dx.doi.org/10.1093/nar/gkq1282
↑ Rorbach J, Nicholls TJ, Minczuk M. PDE12 removes mitochondrial RNA poly(A) tails and controls translation in human mitochondria. Nucleic Acids Res. 2011 Sep 1;39(17):7750-63. doi: 10.1093/nar/gkr470. Epub 2011 , Jun 11. PMID:21666256 doi:http://dx.doi.org/10.1093/nar/gkr470
↑ Poulsen JB, Andersen KR, Kjaer KH, Vestergaard AL, Justesen J, Martensen PM. Characterization of human phosphodiesterase 12 and identification of a novel 2'-5' oligoadenylate nuclease - The ectonucleotide pyrophosphatase/phosphodiesterase 1. Biochimie. 2012 May;94(5):1098-107. doi: 10.1016/j.biochi.2012.01.012. Epub 2012 , Jan 24. PMID:22285541 doi:http://dx.doi.org/10.1016/j.biochi.2012.01.012
↑ 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. The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors. J Biol Chem. 2015 Jun 8. pii: jbc.M115.653113. PMID:26055709 doi:http://dx.doi.org/10.1074/jbc.M115.653113

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4z2b"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4z2b]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Z2B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Z2B FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4LC:3-(6-{[(2S,3S)-3-(HYDROXYMETHYL)-2-PHENYLMORPHOLIN-4-YL]CARBONYL}-1-METHYL-1H-BENZIMIDAZOL-2-YL)-1H-INDOLE-6-CARBONITRILE'>4LC</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4LC:3-(6-{[(2S,3S)-3-(HYDROXYMETHYL)-2-PHENYLMORPHOLIN-4-YL]CARBONYL}-1-METHYL-1H-BENZIMIDAZOL-2-YL)-1H-INDOLE-6-CARBONITRILE'>4LC</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4z2b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z2b OCA], [https://pdbe.org/4z2b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4z2b RCSB], [https://www.ebi.ac.uk/pdbsum/4z2b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4z2b ProSAT]</span></td></tr>
 </table>

4z2b

From Proteopedia

Current revision

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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