Contents:
Previous and Unofficial Names  |
| (N7-guanine)-methyltransferase | N7-MTase |
| Database Links |
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| UniProtKB | P0DTD8 (SARS-CoV-2), P59634 (SARS-CoV) |
| Selected 3D Structures |
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Download all structure-activity data for this target as a CSV file 
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| General Comments |
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Nsp14 is a bifunctional enzyme. It is one of two nonstructural proteins that are encoded in the coronavirus RNA genome that have methyltransferase (MTase) activity [3-4,7]. Nsp16 is the other MTase. Nsp14's MTase activity resides in its C-terminal domain, and its N-terminal domain has 3'-to-5' exoribonuclease (ExoN) activity. The MTase activity catalyses the transfer of the methyl group from the S-adenosyl-l-methionine (SAM) cofactor to the N7-guanosine cap on the viral mRNA, yielding S-adenosyl-l-homocysteine (SAH) as a reaction product. Capping the RNA molecules is essential for viral mRNA stability and translation, and it helps the virus to evade the host's innate immune response. Based on evidence from SARS-CoV, ExoN function is proposed to provide a proofreading mechanism during genome replication [3]. SAM/SAH derivatives that act as nsp14 inhibitors are being explored for antiviral activity against SARS-CoV-2 [1,5]. |
References
1. Ahmed-Belkacem R, Hausdorff M, Delpal A, Sutto-Ortiz P, Colmant AMG, Touret F, Ogando NS, Snijder EJ, Canard B, Coutard B et al.. (2022) Potent Inhibition of SARS-CoV-2 nsp14 N7-Methyltransferase by Sulfonamide-Based Bisubstrate Analogues. J Med Chem, 65 (8): 6231-6249. [PMID:35439007]
2. Ma Y, Wu L, Shaw N, Gao Y, Wang J, Sun Y, Lou Z, Yan L, Zhang R, Rao Z. (2015) Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex. Proc Natl Acad Sci U S A, 112 (30): 9436-41. [PMID:26159422]
3. Minskaia E, Hertzig T, Gorbalenya AE, Campanacci V, Cambillau C, Canard B, Ziebuhr J. (2006) Discovery of an RNA virus 3'->5' exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc Natl Acad Sci USA, 103 (13): 5108-13. [PMID:16549795]
4. Ogando NS, Zevenhoven-Dobbe JC, van der Meer Y, Bredenbeek PJ, Posthuma CC, Snijder EJ. (2020) The Enzymatic Activity of the nsp14 Exoribonuclease Is Critical for Replication of MERS-CoV and SARS-CoV-2. J Virol, 94 (23). DOI: 10.1128/JVI.01246-20 [PMID:32938769]
5. Otava T, Šála M, Li F, Fanfrlík J, Devkota K, Perveen S, Chau I, Pakarian P, Hobza P, Vedadi M et al.. (2021) The Structure-Based Design of SARS-CoV-2 nsp14 Methyltransferase Ligands Yields Nanomolar Inhibitors. ACS Infect Dis, 7 (8): 2214-2220. [PMID:34152728]
6. Singh I, Li F, Fink EA, Chau I, Li A, Rodriguez-Hernández A, Glenn I, Zapatero-Belinchón FJ, Rodriguez ML, Devkota K et al.. (2023) Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase. J Med Chem,. DOI: 10.1021/acs.jmedchem.2c02120
7. Snijder EJ, Decroly E, Ziebuhr J. (2016) The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing. Adv Virus Res, 96: 59-126. [PMID:27712628]
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