5tl7
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of SARS-CoV papain-like protease in complex with C-terminal domain mouse ISG15== | |
| + | <StructureSection load='5tl7' size='340' side='right' caption='[[5tl7]], [[Resolution|resolution]] 2.44Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5tl7]] is a 4 chain structure. 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> | ||
| + | </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> | ||
| + | <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='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'>[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> | ||
| + | == 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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:28438633</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 5tl7" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Daczkowski, C D]] | ||
| + | [[Category: Dzimianski, J V]] | ||
| + | [[Category: Pegan, S D]] | ||
| + | [[Category: Hydrolase]] | ||
| + | [[Category: Signaling protein]] | ||
| + | [[Category: Signaling protein-hydrolase complex]] | ||
Revision as of 12:59, 4 May 2017
Crystal structure of SARS-CoV papain-like protease in complex with C-terminal domain mouse ISG15
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