5v69

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Current revision (14:31, 6 March 2024) (edit) (undo)
 
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<StructureSection load='5v69' size='340' side='right'caption='[[5v69]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
<StructureSection load='5v69' size='340' side='right'caption='[[5v69]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5v69]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human] and [http://en.wikipedia.org/wiki/Human_betacoronavirus_2c_emc/2012 Human betacoronavirus 2c emc/2012]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V69 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V69 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5v69]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Human_betacoronavirus_2c_EMC/2012 Human betacoronavirus 2c EMC/2012]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V69 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V69 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PGO:S-1,2-PROPANEDIOL'>PGO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.55&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v6a|5v6a]]</td></tr>
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<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=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PGO:S-1,2-PROPANEDIOL'>PGO</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">orf1ab ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1235996 Human betacoronavirus 2c EMC/2012])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5v69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v69 OCA], [https://pdbe.org/5v69 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v69 RCSB], [https://www.ebi.ac.uk/pdbsum/5v69 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v69 ProSAT]</span></td></tr>
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<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=5v69 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v69 OCA], [http://pdbe.org/5v69 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v69 RCSB], [http://www.ebi.ac.uk/pdbsum/5v69 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v69 ProSAT]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/K0BWD0_MERS K0BWD0_MERS] 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).[ARBA:ARBA00002223] Enzyme possessing two different activities: an exoribonuclease activity acting on both ssRNA and dsRNA in a 3' to 5' direction and a N7-guanine methyltransferase activity.[ARBA:ARBA00003995] 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.[ARBA:ARBA00002182] 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.[ARBA:ARBA00003443] May participate in viral replication by acting as a ssRNA-binding protein.[ARBA:ARBA00002012] 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.[ARBA:ARBA00003115] Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs. N7-methyl guanosine cap is a prerequisite for binding of nsp16. Therefore plays an essential role in viral mRNAs cap methylation which is essential to evade immune system.[ARBA:ARBA00002840] Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium.[ARBA:ARBA00002960] Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.[ARBA:ARBA00003070] 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.[ARBA:ARBA00002697] 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.[ARBA:ARBA00003748] Plays a role in viral transcription/replication and prevents the simultaneous activation of host cell dsRNA sensors, such as MDA5/IFIH1, OAS, and PKR (By similarity). Acts by degrading the 5'-polyuridines generated during replication of the poly(A) region of viral genomic and subgenomic RNAs. Catalyzes a two-step reaction in which a 2'3'-cyclic phosphate (2'3'-cP) is first generated by 2'-O transesterification, which is then hydrolyzed to a 3'-phosphate (3'-P) (By similarity). If not degraded, poly(U) RNA would hybridize with poly(A) RNA tails and activate host dsRNA sensors.[ARBA:ARBA00025521] Responsible for replication and transcription of the viral RNA genome.[ARBA:ARBA00003927] 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.[ARBA:ARBA00003368]
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The recent Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola and Zika virus outbreaks exemplify the continued threat of (re-)emerging viruses to human health, and our inability to rapidly develop effective therapeutic countermeasures. Many viruses, including MERS-CoV and the Crimean-Congo hemorrhagic fever virus (CCHFV) encode deubiquitinating (DUB) enzymes that are critical for viral replication and pathogenicity. They bind and remove ubiquitin (Ub) and interferon stimulated gene 15 (ISG15) from cellular proteins to suppress host antiviral innate immune responses. A variety of viral DUBs (vDUBs), including the MERS-CoV papain-like protease, are responsible for cleaving the viral replicase polyproteins during replication, and are thereby critical components of the viral replication cycle. Together, this makes vDUBs highly attractive antiviral drug targets. However, structural similarity between the catalytic cores of vDUBs and human DUBs complicates the development of selective small molecule vDUB inhibitors. We have thus developed an alternative strategy to target the vDUB activity through a rational protein design approach. Here, we report the use of phage-displayed ubiquitin variant (UbV) libraries to rapidly identify potent and highly selective protein-based inhibitors targeting the DUB domains of MERS-CoV and CCHFV. UbVs bound the vDUBs with high affinity and specificity to inhibit deubiquitination, deISGylation and in the case of MERS-CoV also viral replicative polyprotein processing. Co-crystallization studies further revealed critical molecular interactions between UbVs and MERS-CoV or CCHFV vDUBs, accounting for the observed binding specificity and high affinity. Finally, expression of UbVs during MERS-CoV infection reduced infectious progeny titers by more than four orders of magnitude, demonstrating the remarkable potency of UbVs as antiviral agents. Our results thereby establish a strategy to produce protein-based inhibitors that could protect against a diverse range of viruses by providing UbVs via mRNA or protein delivery technologies or through transgenic techniques.
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Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants.,Zhang W, Bailey-Elkin BA, Knaap RCM, Khare B, Dalebout TJ, Johnson GG, van Kasteren PB, McLeish NJ, Gu J, He W, Kikkert M, Mark BL, Sidhu SS PLoS Pathog. 2017 May 18;13(5):e1006372. doi: 10.1371/journal.ppat.1006372., eCollection 2017 May. PMID:28542609<ref>PMID:28542609</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5v69" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[SARS Coronavirus Main Proteinase|SARS Coronavirus Main Proteinase]]
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*[[Virus protease 3D structures|Virus protease 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Human betacoronavirus 2c emc/2012]]
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[[Category: Human betacoronavirus 2c EMC/2012]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Bailey-Elkin, B A]]
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[[Category: Bailey-Elkin BA]]
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[[Category: Mark, B L]]
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[[Category: Mark BL]]
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[[Category: Dub]]
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[[Category: Hydrolase]]
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[[Category: Plpro]]
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[[Category: Ubiquitin]]
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Current revision

Crystal structure of the Middle East respiratory syndrome coronavirus papain-like protease bound to ubiquitin variant ME.4

PDB ID 5v69

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