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==== | ==SARS-COV-2 nsp1 in complex with human 40S ribosome== | ||
<StructureSection load='7k5i' size='340' side='right'caption='[[7k5i]]' scene=''> | <StructureSection load='7k5i' size='340' side='right'caption='[[7k5i]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id= OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol= FirstGlance]. <br> | <table><tr><td colspan='2'>[[7k5i]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7K5I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7K5I FirstGlance]. <br> | ||
</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=7k5i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k5i OCA], [https://pdbe.org/7k5i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k5i RCSB], [https://www.ebi.ac.uk/pdbsum/7k5i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k5i ProSAT]</span></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.9Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=7k5i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7k5i OCA], [https://pdbe.org/7k5i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7k5i RCSB], [https://www.ebi.ac.uk/pdbsum/7k5i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7k5i ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a highly contagious virus that underlies the current COVID-19 pandemic. SARS-CoV-2 is thought to disable various features of host immunity and cellular defense. The SARS-CoV-2 nonstructural protein 1 (Nsp1) is known to inhibit host protein translation and could be a target for antiviral therapy against COVID-19. However, how SARS-CoV-2 circumvents this translational blockage for the production of its own proteins is an open question. Here, we report a bipartite mechanism of SARS-CoV-2 Nsp1 which operates by: (1) hijacking the host ribosome via direct interaction of its C-terminal domain (CT) with the 40S ribosomal subunit and (2) specifically lifting this inhibition for SARS-CoV-2 via a direct interaction of its N-terminal domain (NT) with the 5' untranslated region (5' UTR) of SARS-CoV-2 mRNA. We show that while Nsp1-CT is sufficient for binding to 40S and inhibition of host protein translation, the 5' UTR of SARS-CoV-2 mRNA removes this inhibition by binding to Nsp1-NT, suggesting that the Nsp1-NT-UTR interaction is incompatible with the Nsp1-CT-40S interaction. Indeed, lengthening the linker between Nsp1-NT and Nsp1-CT of Nsp1 progressively reduced the ability of SARS-CoV-2 5' UTR to escape the translational inhibition, supporting that the incompatibility is likely steric in nature. The short SL1 region of the 5' UTR is required for viral mRNA translation in the presence of Nsp1. Thus, our data provide a comprehensive view on how Nsp1 switches infected cells from host mRNA translation to SARS-CoV-2 mRNA translation, and that Nsp1 and 5' UTR may be targeted for anti-COVID-19 therapeutics. | |||
SARS-CoV-2 Nsp1 suppresses host but not viral translation through a bipartite mechanism.,Shi M, Wang L, Fontana P, Vora S, Zhang Y, Fu TM, Lieberman J, Wu H bioRxiv. 2020 Sep 18. doi: 10.1101/2020.09.18.302901. PMID:32995777<ref>PMID:32995777</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7k5i" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Nonstructural protein 3D structures|Nonstructural protein 3D structures]] | |||
*[[Ribosome 3D structures|Ribosome 3D structures]] | |||
*[[3D sructureseceptor for activated protein kinase C 1|3D sructureseceptor for activated protein kinase C 1]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Shi M]] | ||
[[Category: Wang L]] | |||
[[Category: Wu H]] | |||
Latest revision as of 12:26, 9 October 2024
SARS-COV-2 nsp1 in complex with human 40S ribosomeSARS-COV-2 nsp1 in complex with human 40S ribosome
Structural highlights
Publication Abstract from PubMedThe Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a highly contagious virus that underlies the current COVID-19 pandemic. SARS-CoV-2 is thought to disable various features of host immunity and cellular defense. The SARS-CoV-2 nonstructural protein 1 (Nsp1) is known to inhibit host protein translation and could be a target for antiviral therapy against COVID-19. However, how SARS-CoV-2 circumvents this translational blockage for the production of its own proteins is an open question. Here, we report a bipartite mechanism of SARS-CoV-2 Nsp1 which operates by: (1) hijacking the host ribosome via direct interaction of its C-terminal domain (CT) with the 40S ribosomal subunit and (2) specifically lifting this inhibition for SARS-CoV-2 via a direct interaction of its N-terminal domain (NT) with the 5' untranslated region (5' UTR) of SARS-CoV-2 mRNA. We show that while Nsp1-CT is sufficient for binding to 40S and inhibition of host protein translation, the 5' UTR of SARS-CoV-2 mRNA removes this inhibition by binding to Nsp1-NT, suggesting that the Nsp1-NT-UTR interaction is incompatible with the Nsp1-CT-40S interaction. Indeed, lengthening the linker between Nsp1-NT and Nsp1-CT of Nsp1 progressively reduced the ability of SARS-CoV-2 5' UTR to escape the translational inhibition, supporting that the incompatibility is likely steric in nature. The short SL1 region of the 5' UTR is required for viral mRNA translation in the presence of Nsp1. Thus, our data provide a comprehensive view on how Nsp1 switches infected cells from host mRNA translation to SARS-CoV-2 mRNA translation, and that Nsp1 and 5' UTR may be targeted for anti-COVID-19 therapeutics. SARS-CoV-2 Nsp1 suppresses host but not viral translation through a bipartite mechanism.,Shi M, Wang L, Fontana P, Vora S, Zhang Y, Fu TM, Lieberman J, Wu H bioRxiv. 2020 Sep 18. doi: 10.1101/2020.09.18.302901. PMID:32995777[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
References
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