3PSE: Structure Of A Viral Otu Domain Protease Bound To Interferon- Stimulated Gene 15 (Isg15)

The attachment of ubiquitin (Ub) and the Ub-like (Ubl) molecule interferon-stimulated gene 15 (ISG15) to cellular proteins mediates important innate antiviral responses. Ovarian tumor (OTU) domain proteases from nairoviruses and arteriviruses were recently found to remove these molecules from host proteins, which inhibits Ub and ISG15-dependent antiviral pathways. This contrasts with the Ub-specific activity of known eukaryotic OTU-domain proteases. Here we describe crystal structures of a viral OTU domain from the highly pathogenic Crimean-Congo haemorrhagic fever virus (CCHFV) bound to Ub and to ISG15 at 2.5-A and 2.3-A resolution, respectively. The complexes provide a unique structural example of ISG15 bound to another protein and reveal the molecular mechanism of an ISG15 cross-reactive deubiquitinase. To accommodate structural differences between Ub and ISG15, the viral protease binds the beta-grasp folds of Ub and C-terminal Ub-like domain of ISG15 in an orientation that is rotated nearly 75 degrees with respect to that observed for Ub bound to a representative eukaryotic OTU domain from yeast. Distinct structural determinants necessary for binding either substrate were identified and allowed the reengineering of the viral OTU protease into enzymes with increased substrate specificity, either for Ub or for ISG15. Our findings now provide the basis to determine in vivo the relative contributions of deubiquitination and deISGylation to viral immune evasion tactics, and a structural template of a promiscuous deubiquitinase from a haemorrhagic fever virus that can be targeted for inhibition using small-molecule-based strategies.
PDB ID: 3PSEDownload
MMDB ID: 88116
PDB Deposition Date: 2010/12/1
Updated in MMDB: 2011/05
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Crimean-Congo hemorrhagic fever orthonairovirus
Similar Structures:
Biological Unit for 3PSE: dimeric; determined by author and by software (PISA)
Molecular Components in 3PSE
Label Count Molecule
Proteins (2 molecules)
RNA Polymerase
Molecule annotation
Ubiquitin-like Protein Isg15(Gene symbol: ISG15)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB