SARS-CoV-2 Replicase polyprotein 1ab | SARS-CoV-2 proteins | IUPHAR/BPS Guide to PHARMACOLOGY

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SARS-CoV-2 Replicase polyprotein 1ab

Target not currently curated in GtoImmuPdb

Target id: 3125

Nomenclature: SARS-CoV-2 Replicase polyprotein 1ab

Family: SARS-CoV-2 proteins

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Database Links
UniProtKB
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  1.80 Angstrom Resolution Crystal Structure of NSP16 - NSP10 Complex from SARS-CoV-2
PDB Id:  6W4H
Resolution:  1.8Å
Species:  SARS-CoV-2
References: 
Image of receptor 3D structure from RCSB PDB
Description:  The 1.9 A Crystal Structure of NSP15 Endoribonuclease from SARS CoV-2 in the Complex with a Citrate
PDB Id:  6W01
Resolution:  1.9Å
Species:  SARS-CoV-2
References: 
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of the methyltransferase-stimulatory factor complex of NSP16 and NSP10 from SARS CoV-2.
PDB Id:  6W61
Resolution:  2.0Å
Species:  SARS-CoV-2
References: 
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of NSP15 Endoribonuclease from SARS CoV-2.
PDB Id:  6VWW
Resolution:  2.2Å
Species:  SARS-CoV-2
References: 
General Comments
The pp1ab polyprotein is essentially a pro-protein, that is proteolytically cleaved to form 16 shorter proteins. The first 11 proteins are also cleaved from pp1a. Nsps 12-16 are unique to pp1ab. Most of what is predicted about the functions of these proteins is implied by similarities to orthologues from other coronaviruses [10-11].

Non-structural protein 1 binds to host 40S ribosomes and shuts down host translation [14].

Non-structural protein 2 interacts with host prohibitin (PHB) and prohibitin 2 (PHB2) [7] which may compromise mitochondrial respiration and intracellular survival signalling.

Non-structural protein 3 (papain-like protease, PL-pro) protease activity cleaves motifs at the N-terminus of the replicase polyprotein. PL-pro also removes polyubiquitin chains from cellular substrates, and takes part in the assembly of virally-induced cytoplasmic double-membrane vesicles with nsp4. Blocks host IRF3 activation and NF-κB signalling to down-modulate the host anti-viral immune response. Has potential phosphatase activity [18].

Non-structural protein 4 participates in the assembly of virally-induced cytoplasmic double-membrane vesicles with PL-pro [4].

Non-structural protein 5 is more commonly known as 3CL-protease or main protease (Mpro). It cleaves motifs in the C-terminus of the replicase polyproteins and is crucial for viral replication. Molecular target for the development of inhibitors with anti-coronavirus activity.

Non-structural protein 6 limits autophagosome expansion [8]. This mechanism may favour coronavirus infection by damaging autophagosome-mediated delivery of viral components to lysosomes for degradation.

Non-structural protein 7 forms a hexadecameric complex with nsp8 (8 subunits of each) that appears to be involved in viral replication (primase activity) [21].

Non-structural protein 8 forms a hexadecameric complex with nsp7 (8 subunits of each) that appears to be involved in viral replication (primase activity) [21]

Non-structural protein 9 may be a ssRNA-binding protein that contributes to viral replication [15].

Non-structural protein 10 stimulates nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities, so is essential for viral mRNA cap methylation [6].

Non-structural protein 11 behaves as a RNA-directed RNA polymerase that copies the viral RNA template [3].

Non-structural protein 12 behaves as a 5' to 3' viral helicase that unwinds RNA and DNA duplexes. It has a zinc-binding domain in its N-terminus and its activity is magnesium-dependent [1,12,20]. Cryo-EM resolution of the SARS-CoV-2 polymerase complex architecture shows that it contains the nsp12 catalytic subunit and nsp7-nsp8 co-factors [17]. Small molecule inhibitors of MERS-CoV helicase have been reported [22].

Non-structural protein 13 has proofreading exoribonuclease activity that is required for fidelity during viral RNA synthesis. It also has guanine-N7 methyltransferase activity [2,5-6,9,16,19].

Non-structural protein 14 is a manganese-dependent uridylate-specific endoribonuclease. A nsp10/nsp14 complex exerts potent exoribonuclease activity that may be connected to a replicative mismatch repair mechanism [6]

Non-structural protein 15 (NendoU) is a uridylate-specific endoribonuclease [23]. The catalytic activity of MERS-CoV nsp15 can be modulated by interactions with other nsps (e.g. nsp8 and a nsp7/8 complex), oligomeric assembly and RNA binding efficiency. Nsp15 is essential in coronavirus biology, but interestingly its deletion does not disrupt replication, so its principal action remains elusive. A resolved X-ray structure has been published and deposited with the RCSB Protein Data Bank (6W01) [13]. This shows that enzymatic functional arises from a hexameric complex whose similarity to SARS-CoV nsp15 suggests that inhibitors of this older coronavirus may also inhibit the more recently identified one. MERS-CoV nsp15 inhibitors are considered to be unlikely to inhibit SARS-CoV-2 nsp15.

Non-structural protein 16 is a 2'-O-methyltransferase that mediates 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs..

References

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1. Adedeji AO, Marchand B, Te Velthuis AJ, Snijder EJ, Weiss S, Eoff RL, Singh K, Sarafianos SG. (2012) Mechanism of nucleic acid unwinding by SARS-CoV helicase. PLoS ONE, 7 (5): e36521. [PMID:22615777]

2. Agostini ML, Andres EL, Sims AC, Graham RL, Sheahan TP, Lu X, Smith EC, Case JB, Feng JY, Jordan R et al.. (2018) Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio, 9 (2). DOI: 10.1128/mBio.00221-18 [PMID:29511076]

3. Ahn DG, Choi JK, Taylor DR, Oh JW. (2012) Biochemical characterization of a recombinant SARS coronavirus nsp12 RNA-dependent RNA polymerase capable of copying viral RNA templates. Arch. Virol., 157 (11): 2095-104. [PMID:22791111]

4. Angelini MM, Akhlaghpour M, Neuman BW, Buchmeier MJ. (2013) Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles. mBio, 4 (4). DOI: 10.1128/mBio.00524-13 [PMID:23943763]

5. Bouvet M, Debarnot C, Imbert I, Selisko B, Snijder EJ, Canard B, Decroly E. (2010) In vitro reconstitution of SARS-coronavirus mRNA cap methylation. PLoS Pathog., 6 (4): e1000863. [PMID:20421945]

6. Bouvet M, Imbert I, Subissi L, Gluais L, Canard B, Decroly E. (2012) RNA 3'-end mismatch excision by the severe acute respiratory syndrome coronavirus nonstructural protein nsp10/nsp14 exoribonuclease complex. Proc. Natl. Acad. Sci. U.S.A., 109 (24): 9372-7. [PMID:22635272]

7. Cornillez-Ty CT, Liao L, Yates 3rd JR, Kuhn P, Buchmeier MJ. (2009) Severe acute respiratory syndrome coronavirus nonstructural protein 2 interacts with a host protein complex involved in mitochondrial biogenesis and intracellular signaling. J. Virol., 83 (19): 10314-8. [PMID:19640993]

8. Cottam EM, Whelband MC, Wileman T. (2014) Coronavirus NSP6 restricts autophagosome expansion. Autophagy, 10 (8): 1426-41. [PMID:24991833]

9. Denison MR, Graham RL, Donaldson EF, Eckerle LD, Baric RS. (2011) Coronaviruses: an RNA proofreading machine regulates replication fidelity and diversity. RNA Biol, 8 (2): 270-9. [PMID:21593585]

10. Dong S, Sun J, Mao Z, Wang L, Lu YL, Li J. (2020) A guideline for homology modeling of the proteins from newly discovered betacoronavirus, 2019 novel coronavirus (2019-nCoV). J. Med. Virol., [Epub ahead of print]. [PMID:32181901]

11. Fung TS, Liu DX. (2019) Human Coronavirus: Host-Pathogen Interaction. Annu. Rev. Microbiol., 73: 529-557. [PMID:31226023]

12. Imbert I, Guillemot JC, Bourhis JM, Bussetta C, Coutard B, Egloff MP, Ferron F, Gorbalenya AE, Canard B. (2006) A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. EMBO J., 25 (20): 4933-42. [PMID:17024178]

13. Kim Y, Jedrzejczak R, Maltseva NI, Wilamowski M, Endres M, Godzik A, Michalska K, Joachimiak A. (2020) Crystal structure of Nsp15 endoribonuclease NendoU from SARS-CoV-2. Protein Sci., [Epub ahead of print]. [PMID:32304108]

14. Lokugamage KG, Narayanan K, Huang C, Makino S. (2012) Severe acute respiratory syndrome coronavirus protein nsp1 is a novel eukaryotic translation inhibitor that represses multiple steps of translation initiation. J. Virol., 86 (24): 13598-608. [PMID:23035226]

15. Miknis ZJ, Donaldson EF, Umland TC, Rimmer RA, Baric RS, Schultz LW. (2009) Severe acute respiratory syndrome coronavirus nsp9 dimerization is essential for efficient viral growth. J. Virol., 83 (7): 3007-18. [PMID:19153232]

16. 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. U.S.A., 103 (13): 5108-13. [PMID:16549795]

17. Peng Q, Peng R, Yuan B, Zhao J, Wang M, Wang X, Sun Y, Fan Z, Qi J, Gao GF et al.. (2020) Structural and biochemical characterization of nsp12-nsp7-nsp8 core polymerase complex from SARS-CoV-2. Cell Reports,. DOI: 10.1016/j.celrep.2020.107774

18. Saikatendu KS, Joseph JS, Subramanian V, Clayton T, Griffith M, Moy K, Velasquez J, Neuman BW, Buchmeier MJ, Stevens RC et al.. (2005) Structural basis of severe acute respiratory syndrome coronavirus ADP-ribose-1''-phosphate dephosphorylation by a conserved domain of nsP3. Structure, 13 (11): 1665-75. [PMID:16271890]

19. Smith EC, Blanc H, Surdel MC, Vignuzzi M, Denison MR. (2013) Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog., 9 (8): e1003565. [PMID:23966862]

20. Tanner JA, Watt RM, Chai YB, Lu LY, Lin MC, Peiris JS, Poon LL, Kung HF, Huang JD. (2003) The severe acute respiratory syndrome (SARS) coronavirus NTPase/helicase belongs to a distinct class of 5' to 3' viral helicases. J. Biol. Chem., 278 (41): 39578-82. [PMID:12917423]

21. te Velthuis AJ, van den Worm SH, Snijder EJ. (2012) The SARS-coronavirus nsp7+nsp8 complex is a unique multimeric RNA polymerase capable of both de novo initiation and primer extension. Nucleic Acids Res., 40 (4): 1737-47. [PMID:22039154]

22. Zaher NH, Mostafa MI, Altaher AY. (2020) Design, synthesis and molecular docking of novel triazole derivatives as potential CoV helicase inhibitors. Acta Pharm, 70 (2): 145-159. [PMID:31955138]

23. Zhang L, Li L, Yan L, Ming Z, Jia Z, Lou Z, Rao Z. (2018) Structural and Biochemical Characterization of Endoribonuclease Nsp15 Encoded by Middle East Respiratory Syndrome Coronavirus. J. Virol., 92 (22). [PMID:30135128]

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