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<StructureSection load='5tl7' size='340' side='right'caption='[[5tl7]], [[Resolution|resolution]] 2.44&Aring;' scene=''>
<StructureSection load='5tl7' size='340' side='right'caption='[[5tl7]], [[Resolution|resolution]] 2.44&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5tl7]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/ ] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TL7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TL7 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5tl7]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome-related_coronavirus Severe acute respiratory syndrome-related coronavirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TL7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TL7 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.44&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=AYE:PROP-2-EN-1-AMINE'>AYE</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AYE:PROP-2-EN-1-AMINE'>AYE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tl6|5tl6]], [[5tla|5tla]]</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=5tl7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tl7 OCA], [https://pdbe.org/5tl7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tl7 RCSB], [https://www.ebi.ac.uk/pdbsum/5tl7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tl7 ProSAT]</span></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=10090 LK3 transgenic mice])</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=5tl7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tl7 OCA], [http://pdbe.org/5tl7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tl7 RCSB], [http://www.ebi.ac.uk/pdbsum/5tl7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tl7 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/ISG15_MOUSE ISG15_MOUSE]] Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, TRIM25, STAT5A, MAPK1/ERK2 and globin. Can also isgylate: DDX58/RIG-I which inhibits its function in antiviral signaling response and EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A and B virus, sindbis virus (SV) and herpes simplex type-1 (HHV-1). Plays a significant role in the control of neonatal Chikungunya virus (CHIKV) infection by acting as a putative immunomodulator of proinflammatory cytokines. Protects mice against the consequences of Chikungunya virus infection by downregulating the pathogenic cytokine response, often denoted as the cytokine storm. Plays a role in erythroid differentiation. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity.<ref>PMID:16254333</ref> <ref>PMID:17222803</ref> <ref>PMID:17227866</ref> <ref>PMID:17289916</ref> <ref>PMID:18057259</ref> <ref>PMID:22022510</ref> <ref>PMID:22028657</ref> <ref>PMID:22859821</ref> [[http://www.uniprot.org/uniprot/R1AB_CVHSA R1AB_CVHSA]] The replicase polyprotein of coronaviruses is a multifunctional protein: it contains the activities necessary for the transcription of negative stranded RNA, leader RNA, subgenomic mRNAs and progeny virion RNA as well as proteinases responsible for the cleavage of the polyprotein into functional products (By similarity).<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>  The papain-like proteinase (PL-PRO) is responsible for the cleavages located at the N-terminus of replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF-3.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>  The main proteinase 3CL-PRO is responsible for the majority of cleavages as it cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK (By similarity). Also contains an ADP-ribose-1''-phosphate (ADRP)-binding function.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>  The helicase which contains a zinc finger structure displays RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Its ATPase activity is strongly stimulated by poly(U), poly(dT), poly(C), poly(dA), but not by poly(G). Activity of helicase is dependent on magnesium.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>  The exoribonuclease acts on both ssRNA and dsRNA in a 3' to 5' direction.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>  Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>  Nsp9 is a ssRNA-binding protein.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref>  NendoU is a Mn(2+)-dependent, uridylate-specific enzyme, which leaves 2'-3'-cyclic phosphates 5' to the cleaved bond.<ref>PMID:17024178</ref> <ref>PMID:17692280</ref> <ref>PMID:19369340</ref> 
[https://www.uniprot.org/uniprot/ISG15_MOUSE ISG15_MOUSE] Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, TRIM25, STAT5A, MAPK1/ERK2 and globin. Can also isgylate: DDX58/RIG-I which inhibits its function in antiviral signaling response and EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A and B virus, sindbis virus (SV) and herpes simplex type-1 (HHV-1). Plays a significant role in the control of neonatal Chikungunya virus (CHIKV) infection by acting as a putative immunomodulator of proinflammatory cytokines. Protects mice against the consequences of Chikungunya virus infection by downregulating the pathogenic cytokine response, often denoted as the cytokine storm. Plays a role in erythroid differentiation. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity.<ref>PMID:16254333</ref> <ref>PMID:17222803</ref> <ref>PMID:17227866</ref> <ref>PMID:17289916</ref> <ref>PMID:18057259</ref> <ref>PMID:22022510</ref> <ref>PMID:22028657</ref> <ref>PMID:22859821</ref>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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==See Also==
==See Also==
*[[SARS Coronavirus Main Proteinase|SARS Coronavirus Main Proteinase]]
*[[Virus protease 3D structures|Virus protease 3D structures]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Lk3 transgenic mice]]
[[Category: Mus musculus]]
[[Category: Daczkowski, C D]]
[[Category: Severe acute respiratory syndrome-related coronavirus]]
[[Category: Dzimianski, J V]]
[[Category: Daczkowski CD]]
[[Category: Pegan, S D]]
[[Category: Dzimianski JV]]
[[Category: Hydrolase]]
[[Category: Pegan SD]]
[[Category: Signaling protein]]
[[Category: Signaling protein-hydrolase complex]]

Latest revision as of 16:04, 4 October 2023

Crystal structure of SARS-CoV papain-like protease in complex with C-terminal domain mouse ISG15Crystal structure of SARS-CoV papain-like protease in complex with C-terminal domain mouse ISG15

Structural highlights

5tl7 is a 4 chain structure with sequence from Mus musculus and Severe acute respiratory syndrome-related coronavirus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.44Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ISG15_MOUSE Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, TRIM25, STAT5A, MAPK1/ERK2 and globin. Can also isgylate: DDX58/RIG-I which inhibits its function in antiviral signaling response and EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A and B virus, sindbis virus (SV) and herpes simplex type-1 (HHV-1). Plays a significant role in the control of neonatal Chikungunya virus (CHIKV) infection by acting as a putative immunomodulator of proinflammatory cytokines. Protects mice against the consequences of Chikungunya virus infection by downregulating the pathogenic cytokine response, often denoted as the cytokine storm. Plays a role in erythroid differentiation. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity.[1] [2] [3] [4] [5] [6] [7] [8]

Publication Abstract from PubMed

Severe Acute and Middle East Respiratory syndrome coronaviruses (SARS-CoV and MERS-CoV) encode multifunctional papain-like proteases (PLPs) that have the ability to process the viral polyprotein to facilitate RNA replication as well as antagonize the host innate-immune response. The latter function involves reversing post-translational modification of cellular proteins conjugated with either ubiquitin (Ub) or Ub-like interferon stimulated gene product 15 (ISG15). Ubiquitin is known to be highly conserved among eukaryotes but surprisingly ISG15 is highly divergent among animals. The ramifications of this sequence divergence to recognition of ISG15 by coronaviral papain-like protease at the structural and biochemical levels are poorly understood. Therefore, the activity of PLPs from SARS-CoV, MERS-CoV and mouse hepatitis virus (MHV) was evaluated against seven ISG15s originating from an assortment of animal species susceptible, and not, to certain coronavirus infections. Excitingly, our kinetic, thermodynamic and structural analysis revealed an array of different preferences among PLPs. Included in these studies is the first insight into a coronoavirus PLP's interface with ISG15 via SARS-CoV PLP in complex with the principle binding domain of human and mouse ISG15s. The first X-ray structure of the full-length mouse ISG15 protein is also reported and highlights a unique, twisted-hinge region of ISG15 that is not conserved in human ISG15 suggesting a potential role in differential recognition. Taken together, this new information provides a structural and biochemical understanding of the distinct specificities amongst coronavirus PLPs observed and addresses a critical gap of how PLPs can interact with ISG15s from a wide variety of species.

Structural insights into the interaction of coronavirus papain-like proteases and interferon-stimulated gene product 15 from different species.,Daczkowski CM, Dzimianski JV, Clasman JR, Goodwin O, Mesecar AD, Pegan SD J Mol Biol. 2017 Apr 21. pii: S0022-2836(17)30187-0. doi:, 10.1016/j.jmb.2017.04.011. PMID:28438633[9]

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

See Also

References

  1. ↑ Lenschow DJ, Giannakopoulos NV, Gunn LJ, Johnston C, O'Guin AK, Schmidt RE, Levine B, Virgin HW 4th. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. J Virol. 2005 Nov;79(22):13974-83. PMID:16254333 doi:79/22/13974
  2. ↑ Zou W, Wang J, Zhang DE. Negative regulation of ISG15 E3 ligase EFP through its autoISGylation. Biochem Biophys Res Commun. 2007 Mar 2;354(1):321-7. Epub 2007 Jan 8. PMID:17222803 doi:http://dx.doi.org/10.1016/j.bbrc.2006.12.210
  3. ↑ Lenschow DJ, Lai C, Frias-Staheli N, Giannakopoulos NV, Lutz A, Wolff T, Osiak A, Levine B, Schmidt RE, Garcia-Sastre A, Leib DA, Pekosz A, Knobeloch KP, Horak I, Virgin HW 4th. IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses. Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1371-6. Epub 2007 Jan 16. PMID:17227866 doi:http://dx.doi.org/10.1073/pnas.0607038104
  4. ↑ Okumura F, Zou W, Zhang DE. ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP. Genes Dev. 2007 Feb 1;21(3):255-60. PMID:17289916 doi:http://dx.doi.org/10.1101/gad.1521607
  5. ↑ Kim MJ, Hwang SY, Imaizumi T, Yoo JY. Negative feedback regulation of RIG-I-mediated antiviral signaling by interferon-induced ISG15 conjugation. J Virol. 2008 Feb;82(3):1474-83. Epub 2007 Dec 5. PMID:18057259 doi:http://dx.doi.org/10.1128/JVI.01650-07
  6. ↑ Maragno AL, Pironin M, Alcalde H, Cong X, Knobeloch KP, Tangy F, Zhang DE, Ghysdael J, Quang CT. ISG15 modulates development of the erythroid lineage. PLoS One. 2011;6(10):e26068. doi: 10.1371/journal.pone.0026068. Epub 2011 Oct 12. PMID:22022510 doi:http://dx.doi.org/10.1371/journal.pone.0026068
  7. ↑ Werneke SW, Schilte C, Rohatgi A, Monte KJ, Michault A, Arenzana-Seisdedos F, Vanlandingham DL, Higgs S, Fontanet A, Albert ML, Lenschow DJ. ISG15 is critical in the control of Chikungunya virus infection independent of UbE1L mediated conjugation. PLoS Pathog. 2011 Oct;7(10):e1002322. doi: 10.1371/journal.ppat.1002322. Epub, 2011 Oct 20. PMID:22028657 doi:http://dx.doi.org/10.1371/journal.ppat.1002322
  8. ↑ Bogunovic D, Byun M, Durfee LA, Abhyankar A, Sanal O, Mansouri D, Salem S, Radovanovic I, Grant AV, Adimi P, Mansouri N, Okada S, Bryant VL, Kong XF, Kreins A, Velez MM, Boisson B, Khalilzadeh S, Ozcelik U, Darazam IA, Schoggins JW, Rice CM, Al-Muhsen S, Behr M, Vogt G, Puel A, Bustamante J, Gros P, Huibregtse JM, Abel L, Boisson-Dupuis S, Casanova JL. Mycobacterial disease and impaired IFN-gamma immunity in humans with inherited ISG15 deficiency. Science. 2012 Sep 28;337(6102):1684-8. Epub 2012 Aug 2. PMID:22859821 doi:http://dx.doi.org/10.1126/science.1224026
  9. ↑ Daczkowski CM, Dzimianski JV, Clasman JR, Goodwin O, Mesecar AD, Pegan SD. Structural insights into the interaction of coronavirus papain-like proteases and interferon-stimulated gene product 15 from different species. J Mol Biol. 2017 Apr 21. pii: S0022-2836(17)30187-0. doi:, 10.1016/j.jmb.2017.04.011. PMID:28438633 doi:http://dx.doi.org/10.1016/j.jmb.2017.04.011

5tl7, resolution 2.44Å

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