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3pse

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Structure of a viral OTU domain protease bound to interferon-stimulated gene 15 (ISG15)

Structural highlights

3pse is a 2 chain structure with sequence from Crimean-Congo hemorrhagic fever orthonairovirus and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.3Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

L_CCHFI Displays RNA-directed RNA polymerase, deubiquitinating and deISGylase activities. RNA-dependent RNA polymerase is responsible for replication and transcription of the viral RNA genome. The deubiquitinating activity cleaves both ubiquitinated and ISGylated products and may therefore regulate ubiquitin and ISG15 dependent innate immunity.

Publication Abstract from PubMed

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.

Structural basis for the removal of ubiquitin and interferon-stimulated gene 15 by a viral ovarian tumor domain-containing protease.,James TW, Frias-Staheli N, Bacik JP, Levingston Macleod JM, Khajehpour M, Garcia-Sastre A, Mark BL Proc Natl Acad Sci U S A. 2011 Jan 18. PMID:21245344^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ James TW, Frias-Staheli N, Bacik JP, Levingston Macleod JM, Khajehpour M, Garcia-Sastre A, Mark BL. Structural basis for the removal of ubiquitin and interferon-stimulated gene 15 by a viral ovarian tumor domain-containing protease. Proc Natl Acad Sci U S A. 2011 Jan 18. PMID:21245344 doi:10.1073/pnas.1013388108

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/3pse"

@@ Line 1: / Line 1: @@
 ==Structure of a viral OTU domain protease bound to interferon-stimulated gene 15 (ISG15)==
-<StructureSection load='3pse' size='340' side='right' caption='[[3pse]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='3pse' size='340' side='right'caption='[[3pse]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3pse]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Cchfv Cchfv] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PSE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3PSE FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3pse]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Crimean-Congo_hemorrhagic_fever_orthonairovirus Crimean-Congo hemorrhagic fever orthonairovirus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3PSE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3PSE FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3CN:3-AMINOPROPANE'>3CN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.3&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3pt2|3pt2]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3CN:3-AMINOPROPANE'>3CN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ISG15, G1P2, UCRP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3pse FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pse OCA], [https://pdbe.org/3pse PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3pse RCSB], [https://www.ebi.ac.uk/pdbsum/3pse PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3pse ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3pse FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3pse OCA], [http://pdbe.org/3pse PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3pse RCSB], [http://www.ebi.ac.uk/pdbsum/3pse PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3pse ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/ISG15_HUMAN ISG15_HUMAN]] Ubiquitin-like protein that is conjugated to intracellular target proteins after IFN-alpha or IFN-beta stimulation. Its enzymatic pathway is partially distinct from that of ubiquitin, differing in substrate specificity and interaction with ligating enzymes. ISG15 conjugation pathway uses a dedicated E1 enzyme, but seems to converge with the Ub conjugation pathway at the level of a specific E2 enzyme. Targets include STAT1, SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, EIF2AK2/PKR, MX1/MxA, and RIG-1. Deconjugated by USP18/UBP43. Shows specific chemotactic activity towards neutrophils and activates them to induce release of eosinophil chemotactic factors. May serve as a trans-acting binding factor directing the association of ligated target proteins to intermediate filaments. May also be involved in autocrine, paracrine and endocrine mechanisms, as in cell-to-cell signaling, possibly partly by inducing IFN-gamma secretion by monocytes and macrophages. Seems to display antiviral activity during viral infections.<ref>PMID:1373138</ref> <ref>PMID:7526157</ref> <ref>PMID:8550581</ref> <ref>PMID:2005397</ref> <ref>PMID:16254333</ref> <ref>PMID:16009940</ref>   In response to IFN-tau secreted by the conceptus, may ligate to and regulate proteins involved in the release of prostaglandin F2-alpha (PGF), and thus prevent lysis of the corpus luteum and maintain the pregnancy (By similarity).<ref>PMID:1373138</ref> <ref>PMID:7526157</ref> <ref>PMID:8550581</ref> <ref>PMID:2005397</ref> <ref>PMID:16254333</ref> <ref>PMID:16009940</ref>
+[https://www.uniprot.org/uniprot/L_CCHFI L_CCHFI] Displays RNA-directed RNA polymerase, deubiquitinating and deISGylase activities. RNA-dependent RNA polymerase is responsible for replication and transcription of the viral RNA genome. The deubiquitinating activity cleaves both ubiquitinated and ISGylated products and may therefore regulate ubiquitin and ISG15 dependent innate immunity.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 21: @@
 ==See Also==
-*[[RNA polymerase|RNA polymerase]]
+*[[RNA polymerase 3D structures|RNA polymerase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Cchfv]]
+[[Category: Crimean-Congo hemorrhagic fever orthonairovirus]]
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Bacik, J P]]
+[[Category: Large Structures]]
-[[Category: Frias-Staheli, N]]
+[[Category: Bacik JP]]
-[[Category: Garcia-Sastre, A]]
+[[Category: Frias-Staheli N]]
-[[Category: James, T W]]
+[[Category: Garcia-Sastre A]]
-[[Category: Mark, B L]]
+[[Category: James TW]]
-[[Category: 3-aminopropane]]
+[[Category: Mark BL]]
-[[Category: Crimean-congo hemorrhagic fever virus]]
-[[Category: Hydrolase-protein binding complex]]
-[[Category: Intein-mediated ligation]]
-[[Category: Viral deubiquitinase]]

3pse

From Proteopedia

Current revision

Structure of a viral OTU domain protease bound to interferon-stimulated gene 15 (ISG15)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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