ID R1A_SARS2 Reviewed; 4405 AA.
AC P0DTC1;
DT 22-APR-2020, integrated into UniProtKB/Swiss-Prot.
DT 22-APR-2020, sequence version 1.
DT 10-FEB-2021, entry version 6.
DE RecName: Full=Replicase polyprotein 1a;
DE Short=pp1a;
DE AltName: Full=ORF1a polyprotein;
DE Contains:
DE RecName: Full=Host translation inhibitor nsp1;
DE AltName: Full=Leader protein;
DE AltName: Full=Non-structural protein 1;
DE Short=nsp1;
DE Contains:
DE RecName: Full=Non-structural protein 2;
DE Short=nsp2;
DE AltName: Full=p65 homolog;
DE Contains:
DE RecName: Full=Non-structural protein 3;
DE Short=nsp3;
DE EC=3.4.19.12 {ECO:0000269|PubMed:32726803};
DE EC=3.4.22.-;
DE AltName: Full=PL2-PRO;
DE AltName: Full=Papain-like protease {ECO:0000303|PubMed:32726803};
DE AltName: Full=Papain-like proteinase;
DE Short=PL-PRO;
DE Contains:
DE RecName: Full=Non-structural protein 4;
DE Short=nsp4;
DE Contains:
DE RecName: Full=3C-like proteinase;
DE Short=3CL-PRO;
DE Short=3CLp;
DE EC=3.4.22.69;
DE AltName: Full=Main protease;
DE Short=Mpro {ECO:0000303|PubMed:32272481};
DE AltName: Full=Non-structural protein 5;
DE Short=nsp5;
DE AltName: Full=SARS coronavirus main proteinase;
DE Contains:
DE RecName: Full=Non-structural protein 6;
DE Short=nsp6;
DE Contains:
DE RecName: Full=Non-structural protein 7;
DE Short=nsp7;
DE Contains:
DE RecName: Full=Non-structural protein 8;
DE Short=nsp8;
DE Contains:
DE RecName: Full=Non-structural protein 9;
DE Short=nsp9;
DE Contains:
DE RecName: Full=Non-structural protein 10;
DE Short=nsp10;
DE AltName: Full=Growth factor-like peptide;
DE Short=GFL;
DE Contains:
DE RecName: Full=Non-structural protein 11;
DE Short=nsp11;
OS Severe acute respiratory syndrome coronavirus 2 (2019-nCoV) (SARS-CoV-2).
OC Viruses; Riboviria; Orthornavirae; Pisuviricota; Pisoniviricetes;
OC Nidovirales; Cornidovirineae; Coronaviridae; Orthocoronavirinae;
OC Betacoronavirus; Sarbecovirus.
OX NCBI_TaxID=2697049;
OH NCBI_TaxID=9606; Homo sapiens (Human).
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX PubMed=32015508; DOI=10.1038/s41586-020-2008-3;
RA Wu F., Zhao S., Yu B., Chen Y.-M., Wang W., Song Z.-G., Hu Y., Tao Z.-W.,
RA Tian J.-H., Pei Y.-Y., Yuan M.-L., Zhang Y.-L., Dai F.-H., Liu Y.,
RA Wang Q.-M., Zheng J.-J., Xu L., Holmes E.C., Zhang Y.-Z.;
RT "A new coronavirus associated with human respiratory disease in China.";
RL Nature 579:265-269(2020).
RN [2]
RP X-RAY CRYSTALLOGRAPHY (2.16 ANGSTROMS) OF 3C-LIKE PROTEINASE AND IN COMPLEX
RP WITH MICHAEL ACCEPTOR INHIBITOR N3.
RA Liu X., Zhang B., Jin Z., Yang H., Rao Z.;
RT "The crystal structure of 2019-nCoV main protease in complex with an
RT inhibitor N3.";
RL Submitted (FEB-2020) to the PDB data bank.
RN [3]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF 3C-LIKE PROTEINASE IN COMPLEX
RP WITH ALPHA-KETOAMIDE INHIBITORS, SUBUNIT (3C-LIKE PROTEINASE), ACTIVE SITE,
RP AND ACTIVITY REGULATION.
RX PubMed=32198291; DOI=10.1126/science.abb3405;
RA Zhang L., Lin D., Sun X., Curth U., Drosten C., Sauerhering L., Becker S.,
RA Rox K., Hilgenfeld R.;
RT "Crystal structure of SARS-CoV-2 main protease provides a basis for design
RT of improved alpha-ketoamide inhibitors.";
RL Science 0:0-0(2020).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 3C-LIKE PROTEINASE APOENZYME AND
RP IN COMPLEX WITH MICHAEL ACCEPTOR INHIBITOR N3, FUNCTION, AND CATALYTIC
RP ACTIVITY.
RX PubMed=32272481; DOI=10.1038/s41586-020-2223-y;
RA Jin Z., Du X., Xu Y., Deng Y., Liu M., Zhao Y., Zhang B., Li X., Zhang L.,
RA Peng C., Duan Y., Yu J., Wang L., Yang K., Liu F., Jiang R., Yang X.,
RA You T., Liu X., Yang X., Bai F., Liu H., Liu X., Guddat L.W., Xu W.,
RA Xiao G., Qin C., Shi Z., Jiang H., Rao Z., Yang H.;
RT "Structure of Mpro from COVID-19 virus and discovery of its inhibitors.";
RL Nature 0:0-0(2020).
RN [5]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.9 ANGSTROMS) OF NON-STRUCTURAL PROTEIN
RP 7 AND NON-STRUCTURAL PROTEIN 8, SUBUNIT (NON-STRUCTURAL PROTEIN 7), SUBUNIT
RP (NON-STRUCTURAL PROTEIN 8), FUNCTION (NON-STRUCTURAL PROTEIN 7), AND
RP FUNCTION (NON-STRUCTURAL PROTEIN 8).
RX PubMed=32277040; DOI=10.1126/science.abb7498;
RA Gao Y., Yan L., Huang Y., Liu F., Zhao Y., Cao L., Wang T., Sun Q.,
RA Ming Z., Zhang L., Ge J., Zheng L., Zhang Y., Wang H., Zhu Y., Zhu C.,
RA Hu T., Hua T., Zhang B., Yang X., Li J., Yang H., Liu Z., Xu W.,
RA Guddat L.W., Wang Q., Lou Z., Rao Z.;
RT "Structure of the RNA-dependent RNA polymerase from COVID-19 virus.";
RL Science 0:0-0(2020).
RN [6]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.5 ANGSTROMS) OF NON-STRUCTURAL PROTEIN
RP 7 AND NON-STRUCTURAL PROTEIN 8, SUBUNIT (NON-STRUCTURAL PROTEIN 7), SUBUNIT
RP (NON-STRUCTURAL PROTEIN 8), FUNCTION (NON-STRUCTURAL PROTEIN 7), AND
RP FUNCTION (NON-STRUCTURAL PROTEIN 8).
RX PubMed=32358203; DOI=10.1126/science.abc1560;
RA Yin W., Mao C., Luan X., Shen D.D., Shen Q., Su H., Wang X., Zhou F.,
RA Zhao W., Gao M., Chang S., Xie Y.C., Tian G., Jiang H.W., Tao S.C.,
RA Shen J., Jiang Y., Jiang H., Xu Y., Zhang S., Zhang Y., Xu H.E.;
RT "Structural basis for inhibition of the RNA-dependent RNA polymerase from
RT SARS-CoV-2 by remdesivir.";
RL Science 0:0-0(2020).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 3C-LIKE PROTEINASE APOENZYME IN
RP COMPLEX WITH COMPOUND 11A AND COMPOUND 11B, FUNCTION (3C-LIKE PROTEINASE),
RP CATALYTIC ACTIVITY (3C-LIKE PROTEINASE), AND ACTIVITY REGULATION (3C-LIKE
RP PROTEINASE).
RX PubMed=32321856; DOI=10.1126/science.abb4489;
RA Dai W., Zhang B., Su H., Li J., Zhao Y., Xie X., Jin Z., Liu F., Li C.,
RA Li Y., Bai F., Wang H., Cheng X., Cen X., Hu S., Yang X., Wang J., Liu X.,
RA Xiao G., Jiang H., Rao Z., Zhang L.K., Xu Y., Yang H., Liu H.;
RT "Structure-based design of antiviral drug candidates targeting the SARS-
RT CoV-2 main protease.";
RL Science 0:0-0(2020).
RN [8]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.9 ANGSTROMS) OF NON-STRUCTURAL PROTEIN
RP 7 AND NON-STRUCTURAL PROTEIN 8, SUBUNIT (NON-STRUCTURAL PROTEIN 7), SUBUNIT
RP (NON-STRUCTURAL PROTEIN 8), FUNCTION (NON-STRUCTURAL PROTEIN 7), AND
RP FUNCTION (NON-STRUCTURAL PROTEIN 8).
RX PubMed=32438371; DOI=10.1038/s41586-020-2368-8;
RA Hillen H.S., Kokic G., Farnung L., Dienemann C., Tegunov D., Cramer P.;
RT "Structure of replicating SARS-CoV-2 polymerase.";
RL Nature 0:0-0(2020).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (0.95 ANGSTROMS) OF NON-STRUCTURAL PROTEIN 3 MACRO
RP DOMAIN, AND FUNCTION OF NON-STRUCTURAL PROTEIN 3.
RX PubMed=32578982; DOI=10.1021/acs.biochem.0c00309;
RA Frick D.N., Virdi R.S., Vuksanovic N., Dahal N., Silvaggi N.R.;
RT "Molecular Basis for ADP-ribose Binding to the Mac1 Domain of SARS-CoV-2
RT Nsp3.";
RL Biochemistry 0:0-0(2020).
RN [10]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.93 ANGSTROMS) OF NON-STRUCTURAL PROTEIN
RP 7 AND NON-STRUCTURAL PROTEIN 8 IN COMPLEX WITH ZINC ION, SUBUNIT
RP (NON-STRUCTURAL PROTEIN 7), SUBUNIT (NON-STRUCTURAL PROTEIN 8), FUNCTION
RP (NON-STRUCTURAL PROTEIN 7), AND FUNCTION (NON-STRUCTURAL PROTEIN 8).
RX PubMed=32526208; DOI=10.1016/j.cell.2020.05.034;
RA Wang Q., Wu J., Wang H., Gao Y., Liu Q., Mu A., Ji W., Yan L., Zhu Y.,
RA Zhu C., Fang X., Yang X., Huang Y., Gao H., Liu F., Ge J., Sun Q., Yang X.,
RA Xu W., Liu Z., Yang H., Lou Z., Jiang B., Guddat L.W., Gong P., Rao Z.;
RT "Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase.";
RL Cell 182:417-428(2020).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (3.18 ANGSTROMS) OF NON-STRUCTURAL PROTEIN 3,
RP FUNCTION (NON-STRUCTURAL PROTEIN 3), CATALYTIC ACTIVITY (NON-STRUCTURAL
RP PROTEIN 3), ACTIVITY REGULATION (NON-STRUCTURAL PROTEIN 3), AND MUTAGENESIS
RP OF VAL-1629; PHE-1632; THR-1638; CYS-1674 AND TYR-1831.
RX PubMed=32726803; DOI=10.1038/s41586-020-2601-5;
RA Shin D., Mukherjee R., Grewe D., Bojkova D., Baek K., Bhattacharya A.,
RA Schulz L., Widera M., Mehdipour A.R., Tascher G., Geurink P.P., Wilhelm A.,
RA van der Heden van Noort G.J., Ovaa H., Mueller S., Knobeloch K.P.,
RA Rajalingam K., Schulman B.A., Cinatl J., Hummer G., Ciesek S., Dikic I.;
RT "Papain-like protease regulates SARS-CoV-2 viral spread and innate
RT immunity.";
RL Nature 0:0-0(2020).
RN [12]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.6 ANGSTROMS) OF NON-STRUCTURAL PROTEIN
RP 1, FUNCTION (NON-STRUCTURAL PROTEIN 1), AND MUTAGENESIS OF LYS-164 AND
RP HIS-165.
RX PubMed=32680882; DOI=10.1126/science.abc8665;
RA Thoms M., Buschauer R., Ameismeier M., Koepke L., Denk T.,
RA Hirschenberger M., Kratzat H., Hayn M., Mackens-Kiani T., Cheng J.,
RA Straub J.H., Stuerzel C.M., Froehlich T., Berninghausen O., Becker T.,
RA Kirchhoff F., Sparrer K.M.J., Beckmann R.;
RT "Structural basis for translational shutdown and immune evasion by the Nsp1
RT protein of SARS-CoV-2.";
RL Science 0:0-0(2020).
RN [13]
RP FUNCTION (NON-STRUCTURAL PROTEIN 1).
RX PubMed=32733001; DOI=10.1038/s41467-020-17665-9;
RA Lei X., Dong X., Ma R., Wang W., Xiao X., Tian Z., Wang C., Wang Y., Li L.,
RA Ren L., Guo F., Zhao Z., Zhou Z., Xiang Z., Wang J.;
RT "Activation and evasion of type I interferon responses by SARS-CoV-2.";
RL Nat. Commun. 11:3810-3810(2020).
RN [14]
RP FUNCTION (NON-STRUCTURAL PROTEIN 1), FUNCTION (NON-STRUCTURAL PROTEIN 6),
RP AND INTERACTION WITH HOST TBK1 (NON-STRUCTURAL PROTEIN 6).
RX PubMed=32979938; DOI=10.1016/j.celrep.2020.108234;
RA Xia H., Cao Z., Xie X., Zhang X., Chen J.Y., Wang H., Menachery V.D.,
RA Rajsbaum R., Shi P.Y.;
RT "Evasion of Type I Interferon by SARS-CoV-2.";
RL Cell Rep. 33:108234-108234(2020).
RN [15]
RP SUBCELLULAR LOCATION (NON-STRUCTURAL PROTEIN 1), SUBCELLULAR LOCATION
RP (NON-STRUCTURAL PROTEIN 2), SUBCELLULAR LOCATION (3C-LIKE PROTEINASE),
RP SUBCELLULAR LOCATION (NON-STRUCTURAL PROTEIN 7), SUBCELLULAR LOCATION
RP (NON-STRUCTURAL PROTEIN 8), SUBCELLULAR LOCATION (NON-STRUCTURAL PROTEIN
RP 9), AND SUBCELLULAR LOCATION (NON-STRUCTURAL PROTEIN 10).
RX PubMed=33060197; DOI=10.1126/science.abe9403;
RG QCRG Structural Biology Consortium;
RG Zoonomia Consortium;
RA Gordon D.E., Hiatt J., Bouhaddou M., Rezelj V.V., Ulferts S., Braberg H.,
RA Jureka A.S., Obernier K., Guo J.Z., Batra J., Kaake R.M., Weckstein A.R.,
RA Owens T.W., Gupta M., Pourmal S., Titus E.W., Cakir M., Soucheray M.,
RA McGregor M., Cakir Z., Jang G., O'Meara M.J., Tummino T.A., Zhang Z.,
RA Foussard H., Rojc A., Zhou Y., Kuchenov D., Huettenhain R., Xu J.,
RA Eckhardt M., Swaney D.L., Fabius J.M., Ummadi M., Tutuncuoglu B.,
RA Rathore U., Modak M., Haas P., Haas K.M., Naing Z.Z.C., Pulido E.H.,
RA Shi Y., Barrio-Hernandez I., Memon D., Petsalaki E., Dunham A.,
RA Marrero M.C., Burke D., Koh C., Vallet T., Silvas J.A., Azumaya C.M.,
RA Billesboelle C., Brilot A.F., Campbell M.G., Diallo A., Dickinson M.S.,
RA Diwanji D., Herrera N., Hoppe N., Kratochvil H.T., Liu Y., Merz G.E.,
RA Moritz M., Nguyen H.C., Nowotny C., Puchades C., Rizo A.N.,
RA Schulze-Gahmen U., Smith A.M., Sun M., Young I.D., Zhao J., Asarnow D.,
RA Biel J., Bowen A., Braxton J.R., Chen J., Chio C.M., Chio U.S.,
RA Deshpande I., Doan L., Faust B., Flores S., Jin M., Kim K., Lam V.L.,
RA Li F., Li J., Li Y.L., Li Y., Liu X., Lo M., Lopez K.E., Melo A.A.,
RA Moss F.R. III, Nguyen P., Paulino J., Pawar K.I., Peters J.K.,
RA Pospiech T.H. Jr., Safari M., Sangwan S., Schaefer K., Thomas P.V.,
RA Thwin A.C., Trenker R., Tse E., Tsui T.K.M., Wang F., Whitis N., Yu Z.,
RA Zhang K., Zhang Y., Zhou F., Saltzberg D., Hodder A.J., Shun-Shion A.S.,
RA Williams D.M., White K.M., Rosales R., Kehrer T., Miorin L., Moreno E.,
RA Patel A.H., Rihn S., Khalid M.M., Vallejo-Gracia A., Fozouni P.,
RA Simoneau C.R., Roth T.L., Wu D., Karim M.A., Ghoussaini M., Dunham I.,
RA Berardi F., Weigang S., Chazal M., Park J., Logue J., McGrath M.,
RA Weston S., Haupt R., Hastie C.J., Elliott M., Brown F., Burness K.A.,
RA Reid E., Dorward M., Johnson C., Wilkinson S.G., Geyer A., Giesel D.M.,
RA Baillie C., Raggett S., Leech H., Toth R., Goodman N., Keough K.C.,
RA Lind A.L., Klesh R.J., Hemphill K.R., Carlson-Stevermer J., Oki J.,
RA Holden K., Maures T., Pollard K.S., Sali A., Agard D.A., Cheng Y.,
RA Fraser J.S., Frost A., Jura N., Kortemme T., Manglik A., Southworth D.R.,
RA Stroud R.M., Alessi D.R., Davies P., Frieman M.B., Ideker T., Abate C.,
RA Jouvenet N., Kochs G., Shoichet B., Ott M., Palmarini M., Shokat K.M.,
RA Garcia-Sastre A., Rassen J.A., Grosse R., Rosenberg O.S., Verba K.A.,
RA Basler C.F., Vignuzzi M., Peden A.A., Beltrao P., Krogan N.J.;
RT "Comparative host-coronavirus protein interaction networks reveal pan-viral
RT disease mechanisms.";
RL Science 0:0-0(2020).
RN [16]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.8 ANGSTROMS) OF NON-STRUCTURAL PROTEIN
RP 1, FUNCTION (NON-STRUCTURAL PROTEIN 1), AND MUTAGENESIS OF
RP 154-TYR--PHE-157; 164-LYS-HIS-165 AND 171-ARG--ARG-175.
RX PubMed=32908316; DOI=10.1038/s41594-020-0511-8;
RA Schubert K., Karousis E.D., Jomaa A., Scaiola A., Echeverria B.,
RA Gurzeler L.A., Leibundgut M., Thiel V., Muehlemann O., Ban N.;
RT "SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation.";
RL Nat. Struct. Mol. Biol. 27:959-966(2020).
CC -!- FUNCTION: [Replicase polyprotein 1a]: Multifunctional protein involved
CC in the transcription and replication of viral RNAs. Contains the
CC proteinases responsible for the cleavages of the polyprotein.
CC {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- FUNCTION: [Host translation inhibitor nsp1]: Inhibits host translation
CC by interacting with binds to the host 40S subunit in ribosomal
CC complexes, including the 43S pre-initiation complex and the non-
CC translating 80S ribosome (PubMed:32680882,PubMed:32908316). The C-
CC terminus binds to and obstructs ribosomal mRNA entry tunnel
CC (PubMed:32680882,PubMed:32908316). Thereby inhibits antiviral response
CC triggered by innate immunity or interferons
CC (PubMed:32680882,PubMed:32979938). The nsp1-40S ribosome complex
CC further induces an endonucleolytic cleavage near the 5'UTR of host
CC mRNAs, targeting them for degradation (By similarity). Viral mRNAs less
CC susceptible to nsp1-mediated inhibition of translation, because of
CC their 5'-end leader sequence (PubMed:32908316). By suppressing host
CC gene expression, nsp1 facilitates efficient viral gene expression in
CC infected cells and evasion from host immune response (By similarity).
CC {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32680882,
CC ECO:0000269|PubMed:32908316, ECO:0000269|PubMed:32979938}.
CC -!- FUNCTION: [Non-structural protein 2]: May play a role in the modulation
CC of host cell survival signaling pathway by interacting with host PHB
CC and PHB2. Indeed, these two proteins play a role in maintaining the
CC functional integrity of the mitochondria and protecting cells from
CC various stresses. {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- FUNCTION: [Non-structural protein 3]: Responsible for the cleavages
CC located at the N-terminus of the replicase polyprotein. Participates
CC together with nsp4 in the assembly of virally-induced cytoplasmic
CC double-membrane vesicles necessary for viral replication (By
CC similarity). Antagonizes innate immune induction of type I interferon
CC by blocking the phosphorylation, dimerization and subsequent nuclear
CC translocation of host IRF3 (By similarity) (PubMed:32733001). Prevents
CC also host NF-kappa-B signaling (By similarity). In addition, PL-PRO
CC possesses a deubiquitinating/deISGylating activity and processes both
CC 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular
CC substrates. Cleaves preferentially ISG15 from substrates in vitro
CC (PubMed:32726803). Can play a role in host ADP-ribosylation by binding
CC ADP-ribose (PubMed:32578982). {ECO:0000250|UniProtKB:P0C6X7,
CC ECO:0000269|PubMed:32578982, ECO:0000269|PubMed:32726803,
CC ECO:0000269|PubMed:32733001}.
CC -!- FUNCTION: [Non-structural protein 4]: Participates in the assembly of
CC virally-induced cytoplasmic double-membrane vesicles necessary for
CC viral replication. {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- FUNCTION: [3C-like proteinase]: Cleaves the C-terminus of replicase
CC polyprotein at 11 sites (PubMed:32321856). Recognizes substrates
CC containing the core sequence [ILMVF]-Q-|-[SGACN] (PubMed:32198291,
CC PubMed:32272481). Also able to bind an ADP-ribose-1''-phosphate (ADRP)
CC (By similarity) (PubMed:32198291, PubMed:32272481).
CC {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32198291,
CC ECO:0000269|PubMed:32272481, ECO:0000269|PubMed:32321856}.
CC -!- FUNCTION: [Non-structural protein 6]: Plays a role in the initial
CC induction of autophagosomes from host reticulum endoplasmic (By
CC similarity). Later, limits the expansion of these phagosomes that are
CC no longer able to deliver viral components to lysosomes (By
CC similarity). Binds to host TBK1 without affecting TBK1 phosphorylation;
CC the interaction with TBK1 decreases IRF3 phosphorylation, which leads
CC to reduced IFN-beta production (PubMed:32979938).
CC {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32979938}.
CC -!- FUNCTION: [Non-structural protein 7]: Plays a role in viral RNA
CC synthesis (PubMed:32358203, PubMed:32277040, PubMed:32438371,
CC PubMed:32526208). Forms a hexadecamer with nsp8 (8 subunits of each)
CC that may participate in viral replication by acting as a primase.
CC Alternatively, may synthesize substantially longer products than
CC oligonucleotide primers (By similarity). {ECO:0000250|UniProtKB:P0C6X7,
CC ECO:0000269|PubMed:32277040, ECO:0000269|PubMed:32358203,
CC ECO:0000269|PubMed:32438371, ECO:0000269|PubMed:32526208}.
CC -!- FUNCTION: [Non-structural protein 8]: Plays a role in viral RNA
CC synthesis (PubMed:32358203, PubMed:32277040, PubMed:32438371,
CC PubMed:32526208). Forms a hexadecamer with nsp7 (8 subunits of each)
CC that may participate in viral replication by acting as a primase.
CC Alternatively, may synthesize substantially longer products than
CC oligonucleotide primers (By similarity). {ECO:0000250|UniProtKB:P0C6X7,
CC ECO:0000269|PubMed:32277040, ECO:0000269|PubMed:32358203,
CC ECO:0000269|PubMed:32438371, ECO:0000269|PubMed:32526208}.
CC -!- FUNCTION: [Non-structural protein 9]: May participate in viral
CC replication by acting as a ssRNA-binding protein.
CC {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- FUNCTION: [Non-structural protein 10]: Plays a pivotal role in viral
CC transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16
CC 2'-O-methyltransferase activities. Therefore plays an essential role in
CC viral mRNAs cap methylation. {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- CATALYTIC ACTIVITY: [Non-structural protein 3]:
CC Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide
CC and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-
CC residue protein attached to proteins as an intracellular targeting
CC signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:32726803};
CC -!- CATALYTIC ACTIVITY: [3C-like proteinase]:
CC Reaction=TSAVLQ-|-SGFRK-NH(2) and SGVTFQ-|-GKFKK the two peptides
CC corresponding to the two self-cleavage sites of the SARS 3C-like
CC proteinase are the two most reactive peptide substrates. The enzyme
CC exhibits a strong preference for substrates containing Gln at P1
CC position and Leu at P2 position.; EC=3.4.22.69;
CC Evidence={ECO:0000269|PubMed:32198291, ECO:0000269|PubMed:32272481,
CC ECO:0000269|PubMed:32321856};
CC -!- ACTIVITY REGULATION: [Non-structural protein 3]: Inhibited in vitro by
CC GRL-0617. {ECO:0000269|PubMed:32726803}.
CC -!- ACTIVITY REGULATION: [3C-like proteinase]: Inhibited by pyridone-
CC containing alpha-ketoamides compounds 13a and 13b. In turn, alpha-
CC ketoamide 13b (tert-butyl (1-((S)-1-(((S)-4-(benzylamino)-3,4-dioxo-1-
CC ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)amino)-3-cyclopropyl-1-oxopropan-
CC 2-yl)-2-oxo-1,2-dihydropyridin-3-yl)carbamate) inhibits SARS-CoV-2
CC replication in human lung cells (PubMed:32198291). Inhibited ex vivo by
CC michael acceptor inhibitor N3 (PubMed:32272481). Inhibited ex vivo by
CC compound 11a and 11b (PubMed:32321856). {ECO:0000269|PubMed:32198291,
CC ECO:0000269|PubMed:32272481, ECO:0000269|PubMed:32321856}.
CC -!- SUBUNIT: [Non-structural protein 2]: Interacts with host PHB and PHB2.
CC {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- SUBUNIT: [3C-like proteinase]: 3CL-PRO exists as monomer and homodimer.
CC Only the homodimer shows catalytic activity.
CC {ECO:0000269|PubMed:32198291}.
CC -!- SUBUNIT: [Non-structural protein 4]: Interacts with PL-PRO and nsp6.
CC {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- SUBUNIT: [Non-structural protein 6]: Interacts with host TBK1; this
CC interaction decreases IRF3 phosphorylation by 57%, which leads to
CC reduced IFN-beta production. {ECO:0000269|PubMed:32979938}.
CC -!- SUBUNIT: [Non-structural protein 7]: Eight copies of nsp7 and eight
CC copies of nsp8 assemble to form a heterohexadecamer dsRNA-encircling
CC ring structure (By similarity). Interacts with RNA-directed RNA
CC polymerase (PubMed:32277040, PubMed:32358203, PubMed:32438371,
CC PubMed:32526208). {ECO:0000250|UniProtKB:P0C6X7,
CC ECO:0000269|PubMed:32277040, ECO:0000269|PubMed:32358203,
CC ECO:0000269|PubMed:32438371, ECO:0000269|PubMed:32526208}.
CC -!- SUBUNIT: [Non-structural protein 8]: Eight copies of nsp7 and eight
CC copies of nsp8 assemble to form a heterohexadecamer dsRNA-encircling
CC ring structure (By similarity). Interacts with RNA-directed RNA
CC polymerase (PubMed:32277040, PubMed:32358203, PubMed:32438371,
CC PubMed:32526208). {ECO:0000250|UniProtKB:P0C6X7,
CC ECO:0000269|PubMed:32277040, ECO:0000269|PubMed:32358203,
CC ECO:0000269|PubMed:32438371, ECO:0000269|PubMed:32526208}.
CC -!- SUBUNIT: [Non-structural protein 9]: Is a dimer.
CC {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- SUBUNIT: [Non-structural protein 10]: Forms a dodecamer and interacts
CC with nsp14 and nsp16; these interactions enhance nsp14 and nsp16
CC enzymatic activities. {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- INTERACTION:
CC PRO_0000449645; O75347: TBCA; Xeno; NbExp=2; IntAct=EBI-25475882, EBI-2686341;
CC -!- SUBCELLULAR LOCATION: [Host translation inhibitor nsp1]: Host cytoplasm
CC {ECO:0000269|PubMed:33060197}.
CC -!- SUBCELLULAR LOCATION: [Non-structural protein 2]: Host cytoplasm
CC {ECO:0000269|PubMed:33060197}. Host endosome
CC {ECO:0000269|PubMed:33060197}.
CC -!- SUBCELLULAR LOCATION: [Non-structural protein 3]: Host membrane
CC {ECO:0000250|UniProtKB:P0C6X7}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P0C6X7}. Host cytoplasm
CC {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- SUBCELLULAR LOCATION: [Non-structural protein 4]: Host membrane
CC {ECO:0000250|UniProtKB:P0C6X7}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P0C6X7}. Host cytoplasm
CC {ECO:0000250|UniProtKB:P0C6X7}. Note=Localizes in virally-induced
CC cytoplasmic double-membrane vesicles. {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- SUBCELLULAR LOCATION: [3C-like proteinase]: Host cytoplasm
CC {ECO:0000269|PubMed:33060197}. Host Golgi apparatus
CC {ECO:0000269|PubMed:33060197}.
CC -!- SUBCELLULAR LOCATION: [Non-structural protein 6]: Host membrane
CC {ECO:0000250|UniProtKB:P0C6X7}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- SUBCELLULAR LOCATION: [Non-structural protein 7]: Host cytoplasm, host
CC perinuclear region {ECO:0000250|UniProtKB:P0C6X9}. Host cytoplasm
CC {ECO:0000269|PubMed:33060197}. Host endoplasmic reticulum
CC {ECO:0000269|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are
CC localized in cytoplasmic foci, largely perinuclear. Late in infection,
CC they merge into confluent complexes. {ECO:0000250|UniProtKB:P0C6X9}.
CC -!- SUBCELLULAR LOCATION: [Non-structural protein 8]: Host cytoplasm, host
CC perinuclear region {ECO:0000250|UniProtKB:P0C6X9}. Host cytoplasm
CC {ECO:0000269|PubMed:33060197}. Host endoplasmic reticulum
CC {ECO:0000269|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are
CC localized in cytoplasmic foci, largely perinuclear. Late in infection,
CC they merge into confluent complexes. {ECO:0000250|UniProtKB:P0C6X9}.
CC -!- SUBCELLULAR LOCATION: [Non-structural protein 9]: Host cytoplasm, host
CC perinuclear region {ECO:0000250|UniProtKB:P0C6X9}. Host cytoplasm
CC {ECO:0000269|PubMed:33060197}. Host endoplasmic reticulum
CC {ECO:0000269|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are
CC localized in cytoplasmic foci, largely perinuclear. Late in infection,
CC they merge into confluent complexes. {ECO:0000250|UniProtKB:P0C6X9}.
CC -!- SUBCELLULAR LOCATION: [Non-structural protein 10]: Host cytoplasm, host
CC perinuclear region {ECO:0000250|UniProtKB:P0C6X9}. Host cytoplasm
CC {ECO:0000269|PubMed:33060197}. Host endoplasmic reticulum
CC {ECO:0000269|PubMed:33060197}. Note=nsp7, nsp8, nsp9 and nsp10 are
CC localized in cytoplasmic foci, largely perinuclear. Late in infection,
CC they merge into confluent complexes. {ECO:0000250|UniProtKB:P0C6X9}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Ribosomal frameshifting; Named isoforms=2;
CC Comment=Normal translation results in Replicase polyprotein 1a.
CC Ribosomal frameshifting at the end of this protein occurs at low
CC frequency and produces Replicase polyprotein 1ab.;
CC Name=Replicase polyprotein 1a;
CC IsoId=P0DTC1-1; Sequence=Displayed;
CC Name=Replicase polyprotein 1ab;
CC IsoId=P0DTD1-1; Sequence=External;
CC -!- DOMAIN: The hydrophobic domains (HD) could mediate the membrane
CC association of the replication complex and thereby alter the
CC architecture of the host cell membrane. {ECO:0000250|UniProtKB:P0C6U8}.
CC -!- PTM: Specific enzymatic cleavages in vivo by its own proteases yield
CC mature proteins. 3CL-PRO and PL-PRO proteinases are autocatalytically
CC processed. {ECO:0000250|UniProtKB:P0C6X7}.
CC -!- MISCELLANEOUS: [Replicase polyprotein 1a]: Produced by conventional
CC translation. {ECO:0000250|UniProtKB:P0C6U8}.
CC -!- SIMILARITY: Belongs to the coronaviruses polyprotein 1ab family.
CC {ECO:0000305}.
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DR EMBL; MN908947; QHD43415.1; ALT_FRAME; Genomic_RNA.
DR RefSeq; YP_009725295.1; NC_045512.2.
DR PDB; 6Y2E; X-ray; 1.75 A; A=3264-3569.
DR PDB; 6Y2F; X-ray; 2.16 A; A=3264-3569.
DR PDB; 6Y2G; X-ray; 2.16 A; A=3264-3569.
DR PDB; 6YHU; X-ray; 2.00 A; A/C=3860-3930, B/D=4018-4134.
DR PDB; 6YYT; EM; 2.90 A; B=3948-4133, C=3860-3932.
DR PDB; 7BV2; EM; 2.50 A; C=3860-3942, B=3943-4140.
DR PDB; 7D3I; X-ray; 2.00 A; A=3264-3569.
DR PDB; 7D47; X-ray; 1.97 A; A/B=1564-1880.
DR PDB; 7D6H; X-ray; 1.60 A; A=1563-1878.
DR PDB; 7D7T; X-ray; 3.15 A; A/B=1563-1878.
DR PDB; 7JIR; X-ray; 2.09 A; A=1564-1878.
DR PDB; 7JIT; X-ray; 1.95 A; A=1564-1878.
DR PDB; 7JIV; X-ray; 2.05 A; A=1564-1878.
DR PDB; 7JIW; X-ray; 2.30 A; A=1564-1878.
DR PDB; 7JN2; X-ray; 1.93 A; A=1564-1878.
DR PDB; 7JRN; X-ray; 2.48 A; A/J=1564-1878.
DR PDBsum; 6Y2E; -.
DR PDBsum; 6Y2F; -.
DR PDBsum; 6Y2G; -.
DR PDBsum; 6YHU; -.
DR PDBsum; 6YYT; -.
DR PDBsum; 7BV2; -.
DR PDBsum; 7D3I; -.
DR PDBsum; 7D47; -.
DR PDBsum; 7D6H; -.
DR PDBsum; 7D7T; -.
DR PDBsum; 7JIR; -.
DR PDBsum; 7JIT; -.
DR PDBsum; 7JIV; -.
DR PDBsum; 7JIW; -.
DR PDBsum; 7JN2; -.
DR PDBsum; 7JRN; -.
DR SASBDB; P0DTC1; -.
DR SMR; P0DTC1; -.
DR BioGRID; 4383866; 4.
DR IntAct; P0DTC1; 37.
DR GeneID; 43740578; -.
DR Reactome; R-HSA-9694271; Assembly of the SARS-CoV-2 Replication-Transcription Complex (RTC).
DR Reactome; R-HSA-9694301; Maturation of replicase proteins.
DR Reactome; R-HSA-9694676; Translation of Replicase and Assembly of the Replication Transcription Complex.
DR Reactome; R-HSA-9694686; Replication of the SARS-CoV-2 genome.
DR Reactome; R-HSA-9694786; Transcription of SARS-CoV-2 sgRNAs.
DR Proteomes; UP000464024; Genome.
DR GO; GO:0039714; C:cytoplasmic viral factory; ISS:UniProtKB.
DR GO; GO:0030430; C:host cell cytoplasm; ISS:UniProtKB.
DR GO; GO:0033644; C:host cell membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0044220; C:host cell perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; ISS:UniProtKB.
DR GO; GO:0008234; F:cysteine-type peptidase activity; IDA:UniProtKB.
DR GO; GO:0004519; F:endonuclease activity; IEA:UniProtKB-KW.
DR GO; GO:0019785; F:ISG15-specific protease activity; ISS:UniProtKB.
DR GO; GO:0046983; F:protein dimerization activity; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0003727; F:single-stranded RNA binding; ISS:UniProtKB.
DR GO; GO:0004843; F:thiol-dependent ubiquitin-specific protease activity; IEA:UniProtKB-EC.
DR GO; GO:0016740; F:transferase activity; IEA:InterPro.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0039595; P:induction by virus of catabolism of host mRNA; IEA:UniProtKB-KW.
DR GO; GO:0039520; P:induction by virus of host autophagy; IEA:UniProtKB-KW.
DR GO; GO:0039519; P:modulation by virus of host autophagy; ISS:UniProtKB.
DR GO; GO:0039648; P:modulation by virus of host protein ubiquitination; IEA:UniProtKB-KW.
DR GO; GO:0039690; P:positive stranded viral RNA replication; ISS:UniProtKB.
DR GO; GO:0016540; P:protein autoprocessing; ISS:UniProtKB.
DR GO; GO:0071108; P:protein K48-linked deubiquitination; ISS:UniProtKB.
DR GO; GO:0070536; P:protein K63-linked deubiquitination; ISS:UniProtKB.
DR GO; GO:0039548; P:suppression by virus of host IRF3 activity; ISS:UniProtKB.
DR GO; GO:0039579; P:suppression by virus of host ISG15 activity; ISS:UniProtKB.
DR GO; GO:0039644; P:suppression by virus of host NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0039722; P:suppression by virus of host toll-like receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0039547; P:suppression by virus of host TRAF activity; ISS:UniProtKB.
DR GO; GO:0039604; P:suppression by virus of host translation; ISS:UniProtKB.
DR GO; GO:0039501; P:suppression by virus of host type I interferon production; ISS:UniProtKB.
DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0019079; P:viral genome replication; IEA:InterPro.
DR GO; GO:0019082; P:viral protein processing; IEA:InterPro.
DR GO; GO:0039694; P:viral RNA genome replication; ISS:UniProtKB.
DR CDD; cd15239; 7tm_YRO2_fungal-like; 1.
DR Gene3D; 1.10.150.420; -; 1.
DR Gene3D; 1.10.1840.10; -; 1.
DR Gene3D; 1.10.8.1190; -; 1.
DR Gene3D; 1.10.8.370; -; 1.
DR Gene3D; 2.30.30.590; -; 1.
DR Gene3D; 2.40.10.10; -; 2.
DR Gene3D; 2.40.10.250; -; 1.
DR Gene3D; 2.40.10.290; -; 1.
DR Gene3D; 3.10.20.350; -; 1.
DR Gene3D; 3.10.20.540; -; 1.
DR Gene3D; 3.40.220.10; -; 1.
DR Gene3D; 3.40.220.20; -; 1.
DR Gene3D; 3.40.220.30; -; 1.
DR Gene3D; 3.40.50.11020; -; 1.
DR Gene3D; 3.90.70.90; -; 1.
DR InterPro; IPR043613; CoV_NSP2_C.
DR InterPro; IPR043615; CoV_NSP2_N.
DR InterPro; IPR043611; CoV_NSP3_C.
DR InterPro; IPR043612; CoV_NSP4_N.
DR InterPro; IPR043610; CoV_NSP6.
DR InterPro; IPR022733; DPUP_SUD_C_bCoV.
DR InterPro; IPR002589; Macro_dom.
DR InterPro; IPR043472; Macro_dom-like.
DR InterPro; IPR042570; NAR_sf.
DR InterPro; IPR036333; NSP10_sf_CoV.
DR InterPro; IPR021590; NSP1_bCoV.
DR InterPro; IPR038030; NSP1_sf_bCoV.
DR InterPro; IPR024375; NSP3_bCoV.
DR InterPro; IPR024358; NSP3_N_bCoV.
DR InterPro; IPR032592; NSP3_NAR_bCoV.
DR InterPro; IPR038166; NSP3_PL2pro_sf_CoV.
DR InterPro; IPR038400; NSP3_SUD-M_sf_bCoV.
DR InterPro; IPR043478; NSP3_SUD-N_bCoV.
DR InterPro; IPR038083; NSP3A-like.
DR InterPro; IPR032505; NSP4_C_CoV.
DR InterPro; IPR038123; NSP4_C_sf_CoV.
DR InterPro; IPR014828; NSP7_CoV.
DR InterPro; IPR037204; NSP7_sf_CoV.
DR InterPro; IPR014829; NSP8_CoV-like.
DR InterPro; IPR037230; NSP8_sf_CoV.
DR InterPro; IPR014822; NSP9_CoV.
DR InterPro; IPR036499; NSP9_sf_CoV.
DR InterPro; IPR013016; Peptidase_C16_CoV.
DR InterPro; IPR008740; Peptidase_C30_CoV.
DR InterPro; IPR043477; Peptidase_C30_dom3_CoV.
DR InterPro; IPR009003; Peptidase_S1_PA.
DR InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin.
DR InterPro; IPR043177; PLpro_N_sf_CoV.
DR InterPro; IPR043503; PLpro_palm_finger_dom_CoV.
DR InterPro; IPR043178; PLpro_thumb_sf_CoV.
DR InterPro; IPR018995; RNA_synth_NSP10_CoV.
DR InterPro; IPR043476; Yro2-like_7TM.
DR Pfam; PF16251; bCoV_NAR; 1.
DR Pfam; PF11501; bCoV_NSP1; 1.
DR Pfam; PF12379; bCoV_NSP3_N; 1.
DR Pfam; PF12124; bCoV_SUD_C; 1.
DR Pfam; PF11633; bCoV_SUD_M; 1.
DR Pfam; PF09401; CoV_NSP10; 1.
DR Pfam; PF19212; CoV_NSP2_C; 1.
DR Pfam; PF19211; CoV_NSP2_N; 1.
DR Pfam; PF19218; CoV_NSP3_C; 1.
DR Pfam; PF16348; CoV_NSP4_C; 1.
DR Pfam; PF19217; CoV_NSP4_N; 1.
DR Pfam; PF19213; CoV_NSP6; 1.
DR Pfam; PF08716; CoV_NSP7; 1.
DR Pfam; PF08717; CoV_NSP8; 1.
DR Pfam; PF08710; CoV_NSP9; 1.
DR Pfam; PF08715; CoV_peptidase; 1.
DR Pfam; PF01661; Macro; 1.
DR Pfam; PF05409; Peptidase_C30; 1.
DR SMART; SM00506; A1pp; 1.
DR SUPFAM; SSF101816; SSF101816; 1.
DR SUPFAM; SSF140367; SSF140367; 1.
DR SUPFAM; SSF143076; SSF143076; 1.
DR SUPFAM; SSF144246; SSF144246; 1.
DR SUPFAM; SSF159936; SSF159936; 1.
DR SUPFAM; SSF160099; SSF160099; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR SUPFAM; SSF52949; SSF52949; 1.
DR PROSITE; PS51942; BCOV_NSP3C_C; 1.
DR PROSITE; PS51941; BCOV_NSP3C_M; 1.
DR PROSITE; PS51945; BCOV_NSP3E_NAB; 1.
DR PROSITE; PS51943; COV_NSP3A_UBL; 1.
DR PROSITE; PS51944; COV_NSP3D_UBL; 1.
DR PROSITE; PS51946; COV_NSP4C; 1.
DR PROSITE; PS00867; CPSASE_2; 1.
DR PROSITE; PS51442; M_PRO; 1.
DR PROSITE; PS51154; MACRO; 1.
DR PROSITE; PS51124; PEPTIDASE_C16; 1.
DR PROSITE; PS51940; SARS_NSP3C_N; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activation of host autophagy by virus;
KW Decay of host mRNAs by virus; Endonuclease;
KW Eukaryotic host gene expression shutoff by virus;
KW Eukaryotic host translation shutoff by virus; Host cytoplasm;
KW Host endoplasmic reticulum; Host endosome;
KW Host gene expression shutoff by virus; Host Golgi apparatus; Host membrane;
KW Host mRNA suppression by virus; Host-virus interaction; Hydrolase;
KW Inhibition of host innate immune response by virus;
KW Inhibition of host interferon signaling pathway by virus;
KW Inhibition of host IRF3 by virus; Inhibition of host ISG15 by virus;
KW Inhibition of host RLR pathway by virus; Membrane; Metal-binding;
KW Modulation of host ubiquitin pathway by viral deubiquitinase;
KW Modulation of host ubiquitin pathway by virus; Nuclease; Protease;
KW Reference proteome; Repeat; Ribosomal frameshifting; RNA-binding;
KW Thiol protease; Transmembrane; Transmembrane helix;
KW Ubl conjugation pathway; Viral immunoevasion; Zinc; Zinc-finger.
FT CHAIN 1..4405
FT /note="Replicase polyprotein 1a"
FT /evidence="ECO:0000250|UniProtKB:P0C6U8"
FT /id="PRO_0000449634"
FT CHAIN 1..180
FT /note="Host translation inhibitor nsp1"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT /id="PRO_0000449635"
FT CHAIN 181..818
FT /note="Non-structural protein 2"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT /id="PRO_0000449636"
FT CHAIN 819..2763
FT /note="Non-structural protein 3"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT /id="PRO_0000449637"
FT CHAIN 2764..3263
FT /note="Non-structural protein 4"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT /id="PRO_0000449638"
FT CHAIN 3264..3569
FT /note="3C-like proteinase"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT /id="PRO_0000449639"
FT CHAIN 3570..3859
FT /note="Non-structural protein 6"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT /id="PRO_0000449640"
FT CHAIN 3860..3942
FT /note="Non-structural protein 7"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT /id="PRO_0000449641"
FT CHAIN 3943..4140
FT /note="Non-structural protein 8"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT /id="PRO_0000449642"
FT CHAIN 4141..4253
FT /note="Non-structural protein 9"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT /id="PRO_0000449643"
FT CHAIN 4254..4392
FT /note="Non-structural protein 10"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT /id="PRO_0000449644"
FT CHAIN 4393..4405
FT /note="Non-structural protein 11"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT /id="PRO_0000449645"
FT TRANSMEM 2226..2246
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 2318..2338
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 2339..2359
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 2361..2381
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 2776..2796
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 3045..3065
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 3077..3097
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 3100..3120
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 3128..3148
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 3165..3185
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 3587..3607
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 3609..3629
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 3635..3655
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 3674..3694
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 3730..3750
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 3779..3799
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 820..929
FT /note="Ubiquitin-like 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214"
FT DOMAIN 1025..1194
FT /note="Macro 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00490"
FT DOMAIN 1231..1359
FT /note="Macro 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00490"
FT DOMAIN 1367..1494
FT /note="Macro 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00490"
FT DOMAIN 1496..1561
FT /note="DPUP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01289"
FT DOMAIN 1565..1620
FT /note="Ubiquitin-like 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00214"
FT DOMAIN 1634..1898
FT /note="Peptidase C16"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00444"
FT DOMAIN 1911..2021
FT /note="Nucleic acid-binding"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01290"
FT DOMAIN 3165..3263
FT /note="Nsp4C"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01291"
FT DOMAIN 3264..3569
FT /note="Peptidase C30"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00772"
FT ZN_FING 1752..1789
FT /note="C4-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00444"
FT REGION 154..180
FT /note="Binding to 40s ribosome mRNA entry channel"
FT /evidence="ECO:0000269|PubMed:32680882"
FT ACT_SITE 1674
FT /note="For PL1-PRO activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00444,
FT ECO:0000269|PubMed:32726803"
FT ACT_SITE 1835
FT /note="For PL2-PRO activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00444"
FT ACT_SITE 3304
FT /note="For 3CL-PRO activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00772,
FT ECO:0000269|PubMed:32198291"
FT ACT_SITE 3408
FT /note="For 3CL-PRO activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00772,
FT ECO:0000269|PubMed:32198291"
FT SITE 180..181
FT /note="Cleavage; by PL-PRO"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT SITE 818..819
FT /note="Cleavage; by PL-PRO"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT SITE 2763..2764
FT /note="Cleavage; by PL-PRO"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT SITE 3263..3264
FT /note="Cleavage; by 3CL-PRO"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT SITE 3569..3570
FT /note="Cleavage; by 3CL-PRO"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT SITE 3859..3860
FT /note="Cleavage; by 3CL-PRO"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT SITE 3942..3943
FT /note="Cleavage; by 3CL-PRO"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT SITE 4140..4141
FT /note="Cleavage; by 3CL-PRO"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT SITE 4253..4254
FT /note="Cleavage; by 3CL-PRO"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT SITE 4392..4393
FT /note="Cleavage; by 3CL-PRO"
FT /evidence="ECO:0000250|UniProtKB:P0C6V3"
FT MUTAGEN 154..157
FT /note="YEDF->AEDA: Complete loss of ribosome binding and
FT cellular translation inhibition."
FT /evidence="ECO:0000269|PubMed:32908316"
FT MUTAGEN 164..165
FT /note="KH->AA: Complete loss of ribosome binding and
FT cellular translation inhibition."
FT /evidence="ECO:0000269|PubMed:32908316"
FT MUTAGEN 164
FT /note="K->A: Complete loss of ribosome binding and cellular
FT translation inhibition."
FT /evidence="ECO:0000269|PubMed:32680882"
FT MUTAGEN 165
FT /note="H->A: Complete loss of ribosome binding and cellular
FT translation inhibition."
FT /evidence="ECO:0000269|PubMed:32680882"
FT MUTAGEN 171..175
FT /note="RELMR->EELME: Complete loss of ribosome binding and
FT cellular translation inhibition."
FT /evidence="ECO:0000269|PubMed:32908316"
FT MUTAGEN 1629
FT /note="V->A: Partial loss of ISG15 cleavage in vitro."
FT /evidence="ECO:0000269|PubMed:32726803"
FT MUTAGEN 1632
FT /note="F->A: Partial loss of ISG15 cleavage in vitro."
FT /evidence="ECO:0000269|PubMed:32726803"
FT MUTAGEN 1638
FT /note="T->A: Partial loss of ubiquitin cleavage in vitro;
FT no effect on ISG15 cleavage in vitro."
FT /evidence="ECO:0000269|PubMed:32726803"
FT MUTAGEN 1638
FT /note="T->L: Increased cleavage of ubiquitin in vitro; no
FT effect on ISG15 cleavage in vitro."
FT /evidence="ECO:0000269|PubMed:32726803"
FT MUTAGEN 1674
FT /note="C->S: Complete loss of PL-pro activity."
FT /evidence="ECO:0000269|PubMed:32726803"
FT MUTAGEN 1831
FT /note="Y->G,T: Reduced inhibition by GRL-0617."
FT /evidence="ECO:0000269|PubMed:32726803"
FT HELIX 3861..3878
FT /evidence="ECO:0000244|PDB:6YHU"
FT HELIX 3881..3883
FT /evidence="ECO:0000244|PDB:6YHU"
FT HELIX 3885..3899
FT /evidence="ECO:0000244|PDB:6YHU"
FT HELIX 3904..3919
FT /evidence="ECO:0000244|PDB:6YHU"
FT TURN 3922..3924
FT /evidence="ECO:0000244|PDB:6YHU"
FT HELIX 3927..3929
FT /evidence="ECO:0000244|PDB:6YHU"
FT HELIX 4019..4040
FT /evidence="ECO:0000244|PDB:6YHU"
FT HELIX 4043..4053
FT /evidence="ECO:0000244|PDB:6YHU"
FT STRAND 4057..4060
FT /evidence="ECO:0000244|PDB:6YHU"
FT STRAND 4070..4074
FT /evidence="ECO:0000244|PDB:6YHU"
FT HELIX 4077..4083
FT /evidence="ECO:0000244|PDB:6YHU"
FT STRAND 4088..4091
FT /evidence="ECO:0000244|PDB:6YHU"
FT STRAND 4094..4102
FT /evidence="ECO:0000244|PDB:6YHU"
FT HELIX 4111..4113
FT /evidence="ECO:0000244|PDB:6YHU"
FT TURN 4116..4118
FT /evidence="ECO:0000244|PDB:6YHU"
FT HELIX 4119..4121
FT /evidence="ECO:0000244|PDB:6YHU"
FT STRAND 4124..4132
FT /evidence="ECO:0000244|PDB:6YHU"
SQ SEQUENCE 4405 AA; 489989 MW; 7F8A21148A7A7E2A CRC64;
MESLVPGFNE KTHVQLSLPV LQVRDVLVRG FGDSVEEVLS EARQHLKDGT CGLVEVEKGV
LPQLEQPYVF IKRSDARTAP HGHVMVELVA ELEGIQYGRS GETLGVLVPH VGEIPVAYRK
VLLRKNGNKG AGGHSYGADL KSFDLGDELG TDPYEDFQEN WNTKHSSGVT RELMRELNGG
AYTRYVDNNF CGPDGYPLEC IKDLLARAGK ASCTLSEQLD FIDTKRGVYC CREHEHEIAW
YTERSEKSYE LQTPFEIKLA KKFDTFNGEC PNFVFPLNSI IKTIQPRVEK KKLDGFMGRI
RSVYPVASPN ECNQMCLSTL MKCDHCGETS WQTGDFVKAT CEFCGTENLT KEGATTCGYL
PQNAVVKIYC PACHNSEVGP EHSLAEYHNE SGLKTILRKG GRTIAFGGCV FSYVGCHNKC
AYWVPRASAN IGCNHTGVVG EGSEGLNDNL LEILQKEKVN INIVGDFKLN EEIAIILASF
SASTSAFVET VKGLDYKAFK QIVESCGNFK VTKGKAKKGA WNIGEQKSIL SPLYAFASEA
ARVVRSIFSR TLETAQNSVR VLQKAAITIL DGISQYSLRL IDAMMFTSDL ATNNLVVMAY
ITGGVVQLTS QWLTNIFGTV YEKLKPVLDW LEEKFKEGVE FLRDGWEIVK FISTCACEIV
GGQIVTCAKE IKESVQTFFK LVNKFLALCA DSIIIGGAKL KALNLGETFV THSKGLYRKC
VKSREETGLL MPLKAPKEII FLEGETLPTE VLTEEVVLKT GDLQPLEQPT SEAVEAPLVG
TPVCINGLML LEIKDTEKYC ALAPNMMVTN NTFTLKGGAP TKVTFGDDTV IEVQGYKSVN
ITFELDERID KVLNEKCSAY TVELGTEVNE FACVVADAVI KTLQPVSELL TPLGIDLDEW
SMATYYLFDE SGEFKLASHM YCSFYPPDED EEEGDCEEEE FEPSTQYEYG TEDDYQGKPL
EFGATSAALQ PEEEQEEDWL DDDSQQTVGQ QDGSEDNQTT TIQTIVEVQP QLEMELTPVV
QTIEVNSFSG YLKLTDNVYI KNADIVEEAK KVKPTVVVNA ANVYLKHGGG VAGALNKATN
NAMQVESDDY IATNGPLKVG GSCVLSGHNL AKHCLHVVGP NVNKGEDIQL LKSAYENFNQ
HEVLLAPLLS AGIFGADPIH SLRVCVDTVR TNVYLAVFDK NLYDKLVSSF LEMKSEKQVE
QKIAEIPKEE VKPFITESKP SVEQRKQDDK KIKACVEEVT TTLEETKFLT ENLLLYIDIN
GNLHPDSATL VSDIDITFLK KDAPYIVGDV VQEGVLTAVV IPTKKAGGTT EMLAKALRKV
PTDNYITTYP GQGLNGYTVE EAKTVLKKCK SAFYILPSII SNEKQEILGT VSWNLREMLA
HAEETRKLMP VCVETKAIVS TIQRKYKGIK IQEGVVDYGA RFYFYTSKTT VASLINTLND
LNETLVTMPL GYVTHGLNLE EAARYMRSLK VPATVSVSSP DAVTAYNGYL TSSSKTPEEH
FIETISLAGS YKDWSYSGQS TQLGIEFLKR GDKSVYYTSN PTTFHLDGEV ITFDNLKTLL
SLREVRTIKV FTTVDNINLH TQVVDMSMTY GQQFGPTYLD GADVTKIKPH NSHEGKTFYV
LPNDDTLRVE AFEYYHTTDP SFLGRYMSAL NHTKKWKYPQ VNGLTSIKWA DNNCYLATAL
LTLQQIELKF NPPALQDAYY RARAGEAANF CALILAYCNK TVGELGDVRE TMSYLFQHAN
LDSCKRVLNV VCKTCGQQQT TLKGVEAVMY MGTLSYEQFK KGVQIPCTCG KQATKYLVQQ
ESPFVMMSAP PAQYELKHGT FTCASEYTGN YQCGHYKHIT SKETLYCIDG ALLTKSSEYK
GPITDVFYKE NSYTTTIKPV TYKLDGVVCT EIDPKLDNYY KKDNSYFTEQ PIDLVPNQPY
PNASFDNFKF VCDNIKFADD LNQLTGYKKP ASRELKVTFF PDLNGDVVAI DYKHYTPSFK
KGAKLLHKPI VWHVNNATNK ATYKPNTWCI RCLWSTKPVE TSNSFDVLKS EDAQGMDNLA
CEDLKPVSEE VVENPTIQKD VLECNVKTTE VVGDIILKPA NNSLKITEEV GHTDLMAAYV
DNSSLTIKKP NELSRVLGLK TLATHGLAAV NSVPWDTIAN YAKPFLNKVV STTTNIVTRC
LNRVCTNYMP YFFTLLLQLC TFTRSTNSRI KASMPTTIAK NTVKSVGKFC LEASFNYLKS
PNFSKLINII IWFLLLSVCL GSLIYSTAAL GVLMSNLGMP SYCTGYREGY LNSTNVTIAT
YCTGSIPCSV CLSGLDSLDT YPSLETIQIT ISSFKWDLTA FGLVAEWFLA YILFTRFFYV
LGLAAIMQLF FSYFAVHFIS NSWLMWLIIN LVQMAPISAM VRMYIFFASF YYVWKSYVHV
VDGCNSSTCM MCYKRNRATR VECTTIVNGV RRSFYVYANG GKGFCKLHNW NCVNCDTFCA
GSTFISDEVA RDLSLQFKRP INPTDQSSYI VDSVTVKNGS IHLYFDKAGQ KTYERHSLSH
FVNLDNLRAN NTKGSLPINV IVFDGKSKCE ESSAKSASVY YSQLMCQPIL LLDQALVSDV
GDSAEVAVKM FDAYVNTFSS TFNVPMEKLK TLVATAEAEL AKNVSLDNVL STFISAARQG
FVDSDVETKD VVECLKLSHQ SDIEVTGDSC NNYMLTYNKV ENMTPRDLGA CIDCSARHIN
AQVAKSHNIA LIWNVKDFMS LSEQLRKQIR SAAKKNNLPF KLTCATTRQV VNVVTTKIAL
KGGKIVNNWL KQLIKVTLVF LFVAAIFYLI TPVHVMSKHT DFSSEIIGYK AIDGGVTRDI
ASTDTCFANK HADFDTWFSQ RGGSYTNDKA CPLIAAVITR EVGFVVPGLP GTILRTTNGD
FLHFLPRVFS AVGNICYTPS KLIEYTDFAT SACVLAAECT IFKDASGKPV PYCYDTNVLE
GSVAYESLRP DTRYVLMDGS IIQFPNTYLE GSVRVVTTFD SEYCRHGTCE RSEAGVCVST
SGRWVLNNDY YRSLPGVFCG VDAVNLLTNM FTPLIQPIGA LDISASIVAG GIVAIVVTCL
AYYFMRFRRA FGEYSHVVAF NTLLFLMSFT VLCLTPVYSF LPGVYSVIYL YLTFYLTNDV
SFLAHIQWMV MFTPLVPFWI TIAYIICIST KHFYWFFSNY LKRRVVFNGV SFSTFEEAAL
CTFLLNKEMY LKLRSDVLLP LTQYNRYLAL YNKYKYFSGA MDTTSYREAA CCHLAKALND
FSNSGSDVLY QPPQTSITSA VLQSGFRKMA FPSGKVEGCM VQVTCGTTTL NGLWLDDVVY
CPRHVICTSE DMLNPNYEDL LIRKSNHNFL VQAGNVQLRV IGHSMQNCVL KLKVDTANPK
TPKYKFVRIQ PGQTFSVLAC YNGSPSGVYQ CAMRPNFTIK GSFLNGSCGS VGFNIDYDCV
SFCYMHHMEL PTGVHAGTDL EGNFYGPFVD RQTAQAAGTD TTITVNVLAW LYAAVINGDR
WFLNRFTTTL NDFNLVAMKY NYEPLTQDHV DILGPLSAQT GIAVLDMCAS LKELLQNGMN
GRTILGSALL EDEFTPFDVV RQCSGVTFQS AVKRTIKGTH HWLLLTILTS LLVLVQSTQW
SLFFFLYENA FLPFAMGIIA MSAFAMMFVK HKHAFLCLFL LPSLATVAYF NMVYMPASWV
MRIMTWLDMV DTSLSGFKLK DCVMYASAVV LLILMTARTV YDDGARRVWT LMNVLTLVYK
VYYGNALDQA ISMWALIISV TSNYSGVVTT VMFLARGIVF MCVEYCPIFF ITGNTLQCIM
LVYCFLGYFC TCYFGLFCLL NRYFRLTLGV YDYLVSTQEF RYMNSQGLLP PKNSIDAFKL
NIKLLGVGGK PCIKVATVQS KMSDVKCTSV VLLSVLQQLR VESSSKLWAQ CVQLHNDILL
AKDTTEAFEK MVSLLSVLLS MQGAVDINKL CEEMLDNRAT LQAIASEFSS LPSYAAFATA
QEAYEQAVAN GDSEVVLKKL KKSLNVAKSE FDRDAAMQRK LEKMADQAMT QMYKQARSED
KRAKVTSAMQ TMLFTMLRKL DNDALNNIIN NARDGCVPLN IIPLTTAAKL MVVIPDYNTY
KNTCDGTTFT YASALWEIQQ VVDADSKIVQ LSEISMDNSP NLAWPLIVTA LRANSAVKLQ
NNELSPVALR QMSCAAGTTQ TACTDDNALA YYNTTKGGRF VLALLSDLQD LKWARFPKSD
GTGTIYTELE PPCRFVTDTP KGPKVKYLYF IKGLNNLNRG MVLGSLAATV RLQAGNATEV
PANSTVLSFC AFAVDAAKAY KDYLASGGQP ITNCVKMLCT HTGTGQAITV TPEANMDQES
FGGASCCLYC RCHIDHPNPK GFCDLKGKYV QIPTTCANDP VGFTLKNTVC TVCGMWKGYG
CSCDQLREPM LQSADAQSFL NGFAV
//