SARS-CoV-2 protein NSP1

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==Structure==
==Structure==
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The 3D structure of Nsp1<ref name="Zhang"> pmid: 32198291</ref><ref name="Semper" pmid; 33319167</ref> consists of a N-terminal domain, a C-terminal domain, and a 20-amino acid long unstructured linker, which flexibly connects the two<ref name="Schubert"/>. The C-terminal domain contains the two α-helices (α1: 154-160, α2: 166-179) and a short loop, which holds the conserved KH-motif (K164 and H165)<ref name="Thoms"/>.
+
The 3D structure of Nsp1<ref name="Zhang"> PMID: 32198291</ref><ref name="Semper" PMID: 33319167</ref> consists of a N-terminal domain, a C-terminal domain, and a 20-amino acid long unstructured linker, which flexibly connects the two<ref name="Schubert"/>. The C-terminal domain contains the two α-helices (α1: 154-160, α2: 166-179) and a short loop, which holds the conserved KH-motif (K164 and H165)<ref name="Thoms"/>.
The C-terminal domain is known to bind inside the mRNA entry channel of the 40S ribosomal subunit. There its α-helix α1 interacts with the ribosomal proteins uS3 and uS5 of 40S, the KH motif with the rRNA helix h18, and α2 with h18 and uS5. Through hydrophobic interactions both α-helices stabilize each other. The surface charge as well as the shape of the C-terminal domain match with the nsp1 interacting parts of 40S, and overlap the mRNA path<ref name="Thoms"/>. While the C-terminal domain is bound to the 40S mRNA channel, the N-terminal domain can move within a ~60 Å radius from its connection to the C-terminal domain<ref name="Schubert"/>.
The C-terminal domain is known to bind inside the mRNA entry channel of the 40S ribosomal subunit. There its α-helix α1 interacts with the ribosomal proteins uS3 and uS5 of 40S, the KH motif with the rRNA helix h18, and α2 with h18 and uS5. Through hydrophobic interactions both α-helices stabilize each other. The surface charge as well as the shape of the C-terminal domain match with the nsp1 interacting parts of 40S, and overlap the mRNA path<ref name="Thoms"/>. While the C-terminal domain is bound to the 40S mRNA channel, the N-terminal domain can move within a ~60 Å radius from its connection to the C-terminal domain<ref name="Schubert"/>.

Revision as of 18:27, 3 February 2022

SARS-CoV-2 protein NS1 (PDB entry 7k3n)

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References

  1. ↑ 1.0 1.1 1.2 Schubert K, Karousis ED, Jomaa A, Scaiola A, Echeverria B, Gurzeler LA, Leibundgut M, Thiel V, Muhlemann O, Ban N. SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation. Nat Struct Mol Biol. 2020 Sep 9. pii: 10.1038/s41594-020-0511-8. doi:, 10.1038/s41594-020-0511-8. PMID:32908316 doi:http://dx.doi.org/10.1038/s41594-020-0511-8
  2. ↑ 2.0 2.1 Yoshimoto FK. The Proteins of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2 or n-COV19), the Cause of COVID-19. Protein J. 2020 Jun;39(3):198-216. doi: 10.1007/s10930-020-09901-4. PMID:32447571 doi:http://dx.doi.org/10.1007/s10930-020-09901-4
  3. ↑ Konkolova E, Klima M, Nencka R, Boura E. Structural analysis of the putative SARS-CoV-2 primase complex. J Struct Biol. 2020 Aug 1;211(2):107548. doi: 10.1016/j.jsb.2020.107548. Epub, 2020 Jun 11. PMID:32535228 doi:http://dx.doi.org/10.1016/j.jsb.2020.107548
  4. ↑ 4.0 4.1 de Lima Menezes G, da Silva RA. Identification of potential drugs against SARS-CoV-2 non-structural protein 1 (nsp1). J Biomol Struct Dyn. 2020 Jul 13:1-11. doi: 10.1080/07391102.2020.1792992. PMID:32657643 doi:http://dx.doi.org/10.1080/07391102.2020.1792992
  5. ↑ Thoms M, Buschauer R, Ameismeier M, Koepke L, Denk T, Hirschenberger M, Kratzat H, Hayn M, Mackens-Kiani T, Cheng J, Straub JH, Sturzel CM, Frohlich T, Berninghausen O, Becker T, Kirchhoff F, Sparrer KMJ, Beckmann R. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science. 2020 Jul 17. pii: science.abc8665. doi: 10.1126/science.abc8665. PMID:32680882 doi:http://dx.doi.org/10.1126/science.abc8665
  6. ↑ Huang C, Lokugamage KG, Rozovics JM, Narayanan K, Semler BL, Makino S. SARS coronavirus nsp1 protein induces template-dependent endonucleolytic cleavage of mRNAs: viral mRNAs are resistant to nsp1-induced RNA cleavage. PLoS Pathog. 2011 Dec;7(12):e1002433. doi: 10.1371/journal.ppat.1002433. Epub, 2011 Dec 8. PMID:22174690 doi:http://dx.doi.org/10.1371/journal.ppat.1002433
  7. ↑ Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors. Science. 2020 Mar 20. pii: science.abb3405. doi: 10.1126/science.abb3405. PMID:32198291 doi:http://dx.doi.org/10.1126/science.abb3405
  8. ↑ consists of a N-terminal domain, a C-terminal domain, and a 20-amino acid long unstructured linker, which flexibly connects the two<ref></ref>. The C-terminal domain contains the two α-helices (α1: 154-160, α2: 166-179) and a short loop, which holds the conserved KH-motif (K164 and H165)<ref></ref>. The C-terminal domain is known to bind inside the mRNA entry channel of the 40S ribosomal subunit. There its α-helix α1 interacts with the ribosomal proteins uS3 and uS5 of 40S, the KH motif with the rRNA helix h18, and α2 with h18 and uS5. Through hydrophobic interactions both α-helices stabilize each other. The surface charge as well as the shape of the C-terminal domain match with the nsp1 interacting parts of 40S, and overlap the mRNA path<ref></ref>. While the C-terminal domain is bound to the 40S mRNA channel, the N-terminal domain can move within a ~60 Å radius from its connection to the C-terminal domain<ref></ref>. To maintain the translation of the viral mRNA, the virus has to circumvent the translational blockage, which is induced by the binding of nsp1 to the 40S mRNA channel<ref></ref>. How this is accomplished is a matter of debate. One suggested way is by using the interaction of the N-terminal domain and the 5’ untranslated region (5’ UTR) of the SARS-CoV-2 mRNA<ref> PMID: 32995777</li> <li id="cite_note-Shi">[[#cite_ref-Shi_0|↑]] <strong class="error">Cite error: Invalid <code>&lt;ref&gt;</code> tag; no text was provided for refs named <code>Shi</code></strong></li></ol></ref>

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