View source for 7ofu


==Structure of SARS-CoV-2 Papain-like protease PLpro in complex with 3, 4-Dihydroxybenzoic acid, methyl ester==
<StructureSection load='7ofu' size='340' side='right'caption='[[7ofu]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7ofu]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7OFU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7OFU FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.72&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HE9:methyl+3,4-bis(oxidanyl)benzoate'>HE9</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=7ofu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ofu OCA], [https://pdbe.org/7ofu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ofu RCSB], [https://www.ebi.ac.uk/pdbsum/7ofu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ofu ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/R1A_SARS2 R1A_SARS2] Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.[UniProtKB:P0C6X7]  Inhibits host translation by interacting with the 40S ribosomal subunit. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. Viral mRNAs are not susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the presence of a 5'-end leader sequence and are therefore protected from degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response.[UniProtKB:P0C6X7]  May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses.[UniProtKB:P0C6X7]  Responsible for the cleavages located at the N-terminus of the 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. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. Prevents also host NF-kappa-B signaling.[UniProtKB:P0C6X7]  Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.[UniProtKB:P0C6X7]  Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Also able to bind an ADP-ribose-1''-phosphate (ADRP).[UniProtKB:P0C6X7]  Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes.[UniProtKB:P0C6X7]  Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7]  Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7]  May participate in viral replication by acting as a ssRNA-binding protein.[UniProtKB:P0C6X7]  Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation.[UniProtKB:P0C6X7]
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host's innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections.

Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease.,Srinivasan V, Brognaro H, Prabhu PR, de Souza EE, Gunther S, Reinke PYA, Lane TJ, Ginn H, Han H, Ewert W, Sprenger J, Koua FHM, Falke S, Werner N, Andaleeb H, Ullah N, Franca BA, Wang M, Barra ALC, Perbandt M, Schwinzer M, Schmidt C, Brings L, Lorenzen K, Schubert R, Machado RRG, Candido ED, Oliveira DBL, Durigon EL, Niebling S, Garcia AS, Yefanov O, Lieske J, Gelisio L, Domaracky M, Middendorf P, Groessler M, Trost F, Galchenkova M, Mashhour AR, Saouane S, Hakanpaa J, Wolf M, Alai MG, Turk D, Pearson AR, Chapman HN, Hinrichs W, Wrenger C, Meents A, Betzel C Commun Biol. 2022 Aug 11;5(1):805. doi: 10.1038/s42003-022-03737-7. PMID:35953531<ref>PMID:35953531</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7ofu" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Alves Franca B]]
[[Category: Andaleeb H]]
[[Category: Awel S]]
[[Category: Betzel C]]
[[Category: Brings L]]
[[Category: Brognaro H]]
[[Category: Chapman HN]]
[[Category: Choudary I]]
[[Category: Ewert W]]
[[Category: Falke S]]
[[Category: Fleckenstein H]]
[[Category: Galchenkova M]]
[[Category: Gelisio L]]
[[Category: Gevorkov Y]]
[[Category: Ginn H]]
[[Category: Groessler M]]
[[Category: Guenther S]]
[[Category: Hakanpaeae J]]
[[Category: Han H]]
[[Category: Hinrichs W]]
[[Category: Koua F]]
[[Category: Lane TJ]]
[[Category: Li C]]
[[Category: Lieske J]]
[[Category: Lorenzen K]]
[[Category: Meents A]]
[[Category: Perbandt M]]
[[Category: Perk A]]
[[Category: Reinke P]]
[[Category: Saouane S]]
[[Category: Schmidt C]]
[[Category: Schubert R]]
[[Category: Schwinzer M]]
[[Category: Sprenger J]]
[[Category: Srinivasan V]]
[[Category: Tolstikova A]]
[[Category: Trost F]]
[[Category: Turk D]]
[[Category: Ullah N]]
[[Category: Wahab A]]
[[Category: Wang M]]
[[Category: Werner N]]
[[Category: Wolf M]]
[[Category: Yefanov O]]