4Z0V

The structure of human PDE12 residues 161-609


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.78 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors.

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.

(2015) J Biol Chem 290: 19681-19696

  • DOI: https://doi.org/10.1074/jbc.M115.653113
  • Primary Citation of Related Structures:  
    4Z0V, 4Z2B

  • 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.


  • Organizational Affiliation

    From the Departments of Biological Sciences and edgar.r.wood@mindspring.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
2',5'-phosphodiesterase 12440Homo sapiensMutation(s): 0 
Gene Names: PDE12
EC: 3.1.4 (PDB Primary Data), 3.1.13.4 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q6L8Q7 (Homo sapiens)
Explore Q6L8Q7 
Go to UniProtKB:  Q6L8Q7
PHAROS:  Q6L8Q7
GTEx:  ENSG00000174840 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ6L8Q7
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.78 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.688α = 90
b = 62.554β = 110.4
c = 65.393γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data collection
SCALEPACKdata scaling
PHASERphasing
PDB_EXTRACTdata extraction
DENZOdata reduction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-06-17
    Type: Initial release
  • Version 1.1: 2015-06-24
    Changes: Database references
  • Version 1.2: 2015-08-19
    Changes: Database references
  • Version 1.3: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description