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6xdc

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<StructureSection load='6xdc' size='340' side='right'caption='[[6xdc]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
<StructureSection load='6xdc' size='340' side='right'caption='[[6xdc]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[6xdc]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/2019-ncov 2019-ncov]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6XDC OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6XDC FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6xdc]] is a 2 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=6XDC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6XDC FirstGlance]. <br>
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</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">3a ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=2697049 2019-nCoV])</td></tr>
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</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=6xdc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xdc OCA], [https://pdbe.org/6xdc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6xdc RCSB], [https://www.ebi.ac.uk/pdbsum/6xdc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6xdc 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://proteopedia.org/fgij/fg.htm?mol=6xdc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6xdc OCA], [http://pdbe.org/6xdc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6xdc RCSB], [http://www.ebi.ac.uk/pdbsum/6xdc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6xdc ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/AP3A_SARS2 AP3A_SARS2]] Forms homotetrameric potassium sensitive ion channels (viroporin) and may modulate virus release. Up-regulates expression of fibrinogen subunits FGA, FGB and FGG in host lung epithelial cells. Induces apoptosis in cell culture. Downregulates the type 1 interferon receptor by inducing serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1) degradation motif and increasing IFNAR1 ubiquitination.[UniProtKB:P59632]
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[[https://www.uniprot.org/uniprot/AP3A_SARS2 AP3A_SARS2]] Forms homotetrameric potassium sensitive ion channels (viroporin) and may modulate virus release. Up-regulates expression of fibrinogen subunits FGA, FGB and FGG in host lung epithelial cells. Induces apoptosis in cell culture. Downregulates the type 1 interferon receptor by inducing serine phosphorylation within the IFN alpha-receptor subunit 1 (IFNAR1) degradation motif and increasing IFNAR1 ubiquitination.[UniProtKB:P59632]
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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SARS-CoV-2 encodes three putative ion channels: E, 8a, and 3a. In related SARS-CoV-1, 3a is implicated in viral release, inflammasome activation, and cell death and its deletion reduces viral titer and morbidity in animal models, suggesting 3a-targeted therapeutics could treat SARS and COVID-19. However, the structural basis for the function of 3a is unknown. Here, we show that SARS-CoV-2 forms large conductance cation channels and present cryo-EM structures of dimeric and tetrameric SARS-CoV-2 3a in lipid nanodiscs. 3a adopts a novel fold and is captured in a closed or inactivated state. A narrow bifurcated exterior pore precludes conduction and leads to a large polar cavity open to the cytosol. 3a function is conserved in a common variant among circulating SARS-CoV-2 that alters the channel pore. We identify 3a-like proteins in Alpha- and Beta-coronaviruses that infect bats and humans, suggesting therapeutics targeting 3a could treat a range of coronaviral diseases.
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SARS-CoV-2 ORF3a is a putative viral ion channel implicated in autophagy inhibition, inflammasome activation and apoptosis. 3a protein and anti-3a antibodies are found in infected patient tissues and plasma. Deletion of 3a in SARS-CoV-1 reduces viral titer and morbidity in mice, suggesting it could be an effective target for vaccines or therapeutics. Here, we present structures of SARS-CoV-2 3a determined by cryo-EM to 2.1-A resolution. 3a adopts a new fold with a polar cavity that opens to the cytosol and membrane through separate water- and lipid-filled openings. Hydrophilic grooves along outer helices could form ion-conduction paths. Using electrophysiology and fluorescent ion imaging of 3a-reconstituted liposomes, we observe Ca(2+)-permeable, nonselective cation channel activity, identify mutations that alter ion permeability and discover polycationic inhibitors of 3a activity. 3a-like proteins are found across coronavirus lineages that infect bats and humans, suggesting that 3a-targeted approaches could treat COVID-19 and other coronavirus diseases.
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Cryo-EM structure of the SARS-CoV-2 3a ion channel in lipid nanodiscs.,Kern DM, Sorum B, Hoel CM, Sridharan S, Remis JP, Toso DB, Brohawn SG bioRxiv. 2020 Jun 18. doi: 10.1101/2020.06.17.156554. PMID:32587976<ref>PMID:32587976</ref>
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Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs.,Kern DM, Sorum B, Mali SS, Hoel CM, Sridharan S, Remis JP, Toso DB, Kotecha A, Bautista DM, Brohawn SG Nat Struct Mol Biol. 2021 Jul;28(7):573-582. doi: 10.1038/s41594-021-00619-0., Epub 2021 Jun 22. PMID:34158638<ref>PMID:34158638</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: 2019-ncov]]
 
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Brohawn, S G]]
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[[Category: Severe acute respiratory syndrome coronavirus 2]]
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[[Category: Hoel, C M]]
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[[Category: Brohawn SG]]
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[[Category: Kern, D M]]
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[[Category: Hoel CM]]
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[[Category: Coronavirus]]
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[[Category: Kern DM]]
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[[Category: Ion channel]]
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[[Category: Sars-cov-2]]
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[[Category: Transport protein]]
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[[Category: Viroporin]]
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Current revision

Cryo-EM structure of SARS-CoV-2 ORF3a

PDB ID 6xdc

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