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PDBsum entry 3pt2
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Hydrolase/protein binding
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PDB id
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3pt2
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References listed in PDB file
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Key reference
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Title
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Structural basis for the removal of ubiquitin and interferon-Stimulated gene 15 by a viral ovarian tumor domain-Containing protease.
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Authors
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T.W.James,
N.Frias-Staheli,
J.P.Bacik,
J.M.Levingston macleod,
M.Khajehpour,
A.García-Sastre,
B.L.Mark.
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Ref.
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Proc Natl Acad Sci U S A, 2011,
108,
2222-2227.
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PubMed id
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Abstract
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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-Å and 2.3-Å 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
β-grasp folds of Ub and C-terminal Ub-like domain of ISG15 in an orientation
that is rotated nearly 75° 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.
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