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   02-DEC-2020, entry version 5.
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).
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 the 40S ribosomal subunit (PubMed:32680882). Nsp1 C
CC       terminus binds to and obstructs ribosomal mRNA entry tunnel
CC       (PubMed:32680882). Thereby inhibits antiviral response triggered by
CC       innate immunity or interferons (PubMed:32680882). The nsp1-40S ribosome
CC       complex further induces an endonucleolytic cleavage near the 5'UTR of
CC       host mRNAs, targeting them for degradation. Viral mRNAs are not
CC       susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the
CC       presence of a 5'-end leader sequence and are therefore protected from
CC       degradation (By similarity). By suppressing host gene expression, nsp1
CC       facilitates efficient viral gene expression in infected cells and
CC       evasion from host immune response (By similarity).
CC       {ECO:0000250|UniProtKB:P0C6X7, ECO:0000269|PubMed:32680882}.
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. Later,
CC       limits the expansion of these phagosomes that are no longer able to
CC       deliver viral components to lysosomes. {ECO:0000250|UniProtKB:P0C6X7}.
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 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   -!- 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: [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}. Note=nsp7, nsp8,
CC       nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear.
CC       Late in infection, they merge into confluent complexes.
CC       {ECO:0000250|UniProtKB:P0C6X9}.
CC   -!- SUBCELLULAR LOCATION: [Non-structural protein 8]: Host cytoplasm, host
CC       perinuclear region {ECO:0000250|UniProtKB:P0C6X9}. Note=nsp7, nsp8,
CC       nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear.
CC       Late in infection, they merge into confluent complexes.
CC       {ECO:0000250|UniProtKB:P0C6X9}.
CC   -!- SUBCELLULAR LOCATION: [Non-structural protein 9]: Host cytoplasm, host
CC       perinuclear region {ECO:0000250|UniProtKB:P0C6X9}. Note=nsp7, nsp8,
CC       nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear.
CC       Late in infection, they merge into confluent complexes.
CC       {ECO:0000250|UniProtKB:P0C6X9}.
CC   -!- SUBCELLULAR LOCATION: [Non-structural protein 10]: Host cytoplasm, host
CC       perinuclear region {ECO:0000250|UniProtKB:P0C6X9}. Note=nsp7, nsp8,
CC       nsp9 and nsp10 are localized in cytoplasmic foci, largely perinuclear.
CC       Late in infection, they merge into confluent complexes.
CC       {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; 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; 7JIR; -.
DR   PDBsum; 7JIT; -.
DR   PDBsum; 7JIV; -.
DR   PDBsum; 7JIW; -.
DR   PDBsum; 7JN2; -.
DR   PDBsum; 7JRN; -.
DR   SMR; P0DTC1; -.
DR   BioGRID; 4383866; 4.
DR   IntAct; P0DTC1; 4.
DR   GeneID; 43740578; -.
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; PS00867; CPSASE_2; 1.
DR   PROSITE; PS51442; M_PRO; 1.
DR   PROSITE; PS51154; MACRO; 1.
DR   PROSITE; PS51124; PEPTIDASE_C16; 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 gene expression shutoff by virus; 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          1025..1194
FT                   /note="Macro"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00490"
FT   DOMAIN          1634..1898
FT                   /note="Peptidase C16"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00444"
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         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         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
//