Recombinant human coronavirus SARS-CoV-2 3CL protease protein (Active)

Target data

Function

Replicase polyprotein 1ab. Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein. Host translation inhibitor nsp1. Inhibits host translation by associating with the open head conformation of the 40S subunit (PubMed:32680882, PubMed:32908316, PubMed:33080218, PubMed:33479166). The C-terminus binds to and obstructs ribosomal mRNA entry tunnel (PubMed:32680882, PubMed:32908316, PubMed:33080218, PubMed:33479166). Thereby inhibits antiviral response triggered by innate immunity or interferons (PubMed:32680882, PubMed:32979938, PubMed:33080218). The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation (By similarity). This inhibits the integrated stress response (ISR) in the infected cell by preventing EIF2S1/eIF2-alpha phosphorylation upstream of stress granule formation and depletes host G3BP1 (PubMed:36534661). Viral mRNAs less susceptible to nsp1-mediated inhibition of translation, because of their 5'-end leader sequence (PubMed:32908316, PubMed:33080218). Non-structural protein 2. Enhances mRNA repression of the 4EHP-GYF2 complex in the host, thereby inhibiting the antiviral response and facilitating SARS-CoV-2 replication. Possibly acts in cooperation with nsp1, which induces ribosome stalling on host mRNA, triggering mRNA repression by the host 4EHP-GYF2 complex which is enhanced by nsp2. Papain-like protease nsp3. Responsible for the cleavages located at the N-terminus of the replicase polyprotein. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication (PubMed:35551511). Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3 (PubMed:32733001). Prevents also host NF-kappa-B signaling (By similarity). In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates (PubMed:32726803). Cleaves preferentially ISG15 from antiviral protein IFIH1 (MDA5), but not RIGI (PubMed:33727702). Can play a role in host ADP-ribosylation by ADP-ribose (PubMed:32578982). Plays a role in the formation and maintenance of double membrane vesicles (DMVs) replication organelles (PubMed:35551511). DMVs are formed by nsp3 and nsp4, while nsp6 zippers ER membranes and connects to lipid droplets (PubMed:35551511). Non-structural protein 4. Plays a role in the formation and maintenance of double membrane vesicles (DMVs) replication organelles (PubMed:35551511). DMVs are formed by nsp3 and nsp4, while nsp6 zippers ER membranes and connects to lipid droplets (PubMed:35551511). 3C-like proteinase nsp5. Cleaves the C-terminus of replicase polyprotein at 11 sites (PubMed:32321856). Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN] (PubMed:32198291, PubMed:32272481). May cleave human NLRP1 in lung epithelial cells, thereby activating the NLRP1 inflammasome pathway (PubMed:35594856). May cleave human GSDMD, triggering alternative GSDME-mediated epithelial cell death upon activation of the NLRP1 inflammasome, which may enhance the release interleukins 1B, 6, 16 and 18 (PubMed:35594856). Also able to bind an ADP-ribose-1''-phosphate (ADRP) (PubMed:32198291, PubMed:32272481). Non-structural protein 6. Plays a role in the formation and maintenance of double membrane vesicles (DMVs) replication organelles (PubMed:35551511). DMVs are formed by nsp3 and nsp4, while nsp6 zippers ER membranes and connects to lipid droplets (PubMed:35551511). LDs are consumed during DMV formation (PubMed:35551511). Binds to host TBK1 without affecting TBK1 phosphorylation; the interaction with TBK1 decreases IRF3 phosphorylation, which leads to reduced IFN-beta production (PubMed:32979938). Non-structural protein 7. Plays a role in viral RNA synthesis (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208). Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers (By similarity). Non-structural protein 8. Plays a role in viral RNA synthesis (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208). Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers (By similarity). Interacts with ribosome signal recognition particle RNA (SRP) (PubMed:33080218). Together with NSP9, suppress protein integration into the cell membrane, thereby disrupting host immune defenses (PubMed:33080218). Viral protein genome-linked nsp9. Forms a primer, NSP9-pU, which is utilized by the polymerase for the initiation of RNA chains (PubMed:37794589). Interacts with ribosome signal recognition particle RNA (SRP) (PubMed:33080218). Together with NSP8, suppress protein integration into the cell membrane, thereby disrupting host immune defenses (PubMed:33080218). Non-structural protein 10. Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease (By similarity) and nsp16 2'-O-methyltransferase activities (PubMed:35944563). Therefore plays an essential role in viral mRNAs cap methylation. RNA-directed RNA polymerase nsp12. RNA-directed RNA polymerase that catalyzes the transcription of viral genomic and subgenomic RNAs. Acts in complex with nsp7 and nsp8 to transcribe both the minus and positive strands of genomic RNA (PubMed:32277040, PubMed:32358203, PubMed:32438371, PubMed:32526208). The kinase-like NiRAN domain of NSP12 attaches one or more nucleotides to the amino terminus of NSP9, forming a covalent RNA-protein intermediate that serves as transcription/replication primer (PubMed:37794589). Subgenomic RNAs (sgRNAs) are formed by discontinuous transcription: The polymerase has the ability to pause at transcription-regulating sequences (TRS) and jump to the leader TRS, resulting in a major deletion (PubMed:35706445). This creates a series of subgenomic RNAs that are replicated, transcribed and translated (PubMed:35706445). In addition, Nsp12 is a subunit of the viral RNA capping enzyme that catalyzes the RNA guanylyltransferase reaction for genomic and sub-genomic RNAs (PubMed:35944563). Subsequently, the NiRAN domain transfers RNA to GDP, and forms the core cap structure GpppA-RNA (PubMed:35944563). Helicase nsp13. Plays a role in viral RNA synthesis (PubMed:33232691). Multi-functional protein with a zinc-binding domain in N-terminus displaying RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Activity of helicase is dependent on magnesium (By similarity). Binds to host TBK1 and inhibits TBK1 phosphorylation; the interaction with TBK1 decreases IRF3 phosphorylation, which leads to reduced IFN-beta production (PubMed:32979938). Guanine-N7 methyltransferase nsp14. Plays a role in viral RNA synthesis through two distinct activities. The N7-guanine methyltransferase activity plays a role in the formation of the cap structure GpppA-RNA (PubMed:35944563). The proofreading exoribonuclease reduces the sensitivity of the virus to RNA mutagens during replication (By similarity). This activity acts on both ssRNA and dsRNA in a 3'-5' direction (By similarity). Uridylate-specific endoribonuclease nsp15. Plays a role in viral transcription/replication and prevents the simultaneous activation of host cell dsRNA sensors, such as MDA5/IFIH1, OAS, and PKR (By similarity). Acts by degrading the 5'-polyuridines generated during replication of the poly(A) region of viral genomic and subgenomic RNAs (PubMed:33504779, PubMed:33564093). Catalyzes a two-step reaction in which a 2'3'-cyclic phosphate (2'3'-cP) is first generated by 2'-O transesterification, which is then hydrolyzed to a 3'-phosphate (3'-P) (PubMed:33504779, PubMed:33564093). If not degraded, poly(U) RNA would hybridize with poly(A) RNA tails and activate host dsRNA sensors (By similarity). May bind genomic dsRNA in association with the replication-transcription complex (RTC), and play a role in nsp12 discontinous transcription (PubMed:34562452, PubMed:35706445). 2'-O-methyltransferase nsp16. Methyltransferase that mediates mRNA cap 2'-O-ribose methylation to the 5'-cap structure of viral mRNAs (PubMed:35944563). N7-methyl guanosine cap is a prerequisite for binding of nsp16 (PubMed:35944563). Therefore plays an essential role in viral mRNAs cap methylation which is essential to evade immune system (PubMed:35944563). May disrupt host mRNA splicing in nucleus by interacting with pre-mRNA Recognition Domains ofthe U1 and U2 snRNAs (PubMed:33080218).

Additional Targets

SARS 3CL protease