ID   L_EBOZM                 Reviewed;        2212 AA.
AC   Q05318; O39794; Q773N0; Q8JS59; Q9DQD1;
DT   01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT   30-MAY-2000, sequence version 2.
DT   24-JAN-2024, entry version 126.
DE   RecName: Full=RNA-directed RNA polymerase L;
DE            Short=Protein L;
DE   AltName: Full=Large structural protein;
DE   AltName: Full=Replicase;
DE   AltName: Full=Transcriptase;
DE   Includes:
DE     RecName: Full=RNA-directed RNA polymerase;
DE              EC=2.7.7.48 {ECO:0000250|UniProtKB:P28887};
DE   Includes:
DE     RecName: Full=GTP phosphohydrolase {ECO:0000250|UniProtKB:P03523};
DE              EC=3.6.1.- {ECO:0000250|UniProtKB:P03523};
DE   Includes:
DE     RecName: Full=GDP polyribonucleotidyltransferase {ECO:0000305};
DE              EC=2.7.7.88 {ECO:0000250|UniProtKB:P03523};
DE     AltName: Full=PRNTase {ECO:0000305};
DE   Includes:
DE     RecName: Full=mRNA cap methyltransferase {ECO:0000305};
DE              EC=2.1.1.375 {ECO:0000250|UniProtKB:P03523};
DE     AltName: Full=mRNA (guanine-N(7)-)-methyltransferase {ECO:0000250|UniProtKB:P03523};
DE              Short=G-N7-MTase {ECO:0000250|UniProtKB:P03523};
DE     AltName: Full=mRNA (nucleoside-2'-O-)-methyltransferase {ECO:0000250|UniProtKB:P03523};
DE              Short=N1-2'-O-MTase {ECO:0000250|UniProtKB:P03523};
GN   Name=L;
OS   Zaire ebolavirus (strain Mayinga-76) (ZEBOV) (Zaire Ebola virus).
OC   Viruses; Riboviria; Orthornavirae; Negarnaviricota; Haploviricotina;
OC   Monjiviricetes; Mononegavirales; Filoviridae; Orthoebolavirus;
OC   Orthoebolavirus zairense; Zaire ebolavirus.
OX   NCBI_TaxID=128952;
OH   NCBI_TaxID=77231; Epomops franqueti (Franquet's epauletted fruit bat) (Epomophorus franqueti).
OH   NCBI_TaxID=9606; Homo sapiens (Human).
OH   NCBI_TaxID=77243; Myonycteris torquata (Little collared fruit bat).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX   PubMed=10073695; DOI=10.1099/0022-1317-80-2-355;
RA   Volchkov V.E., Volchkova V.A., Chepurnov A.A., Blinov V.M., Netesov S.V.,
RA   Feldmann H.;
RT   "Characterization of the L gene and 5' trailer region of Ebola virus.";
RL   J. Gen. Virol. 80:355-362(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA] OF 1-54.
RX   PubMed=8237108; DOI=10.1016/0168-1702(93)90063-s;
RA   Sanchez A., Kiley M.P., Holloway B.P., Auperin D.D.;
RT   "Sequence analysis of the Ebola virus genome: organization, genetic
RT   elements, and comparison with the genome of Marburg virus.";
RL   Virus Res. 29:215-240(1993).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RA   Wilson J.A., Kondig J.P., Kuehne A.I., Hart M.K.;
RL   Submitted (AUG-2002) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH VP35, AND REGION.
RX   PubMed=23582637; DOI=10.1016/j.virol.2013.03.013;
RA   Trunschke M., Conrad D., Enterlein S., Olejnik J., Brauburger K.,
RA   Muehlberger E.;
RT   "The L-VP35 and L-L interaction domains reside in the amino terminus of the
RT   Ebola virus L protein and are potential targets for antivirals.";
RL   Virology 441:135-145(2013).
RN   [5]
RP   FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 742-ASP--GLN-744.
RX   PubMed=28991917; DOI=10.1371/journal.pntd.0005996;
RA   Schmidt M.L., Hoenen T.;
RT   "Characterization of the catalytic center of the Ebola virus L
RT   polymerase.";
RL   PLoS Negl. Trop. Dis. 11:E0005996-E0005996(2017).
RN   [6]
RP   FUNCTION, MUTAGENESIS OF ASP-742, AND COFACTOR.
RX   PubMed=29507309; DOI=10.1038/s41598-018-22328-3;
RA   Tchesnokov E.P., Raeisimakiani P., Ngure M., Marchant D., Goette M.;
RT   "Recombinant RNA-Dependent RNA Polymerase Complex of Ebola Virus.";
RL   Sci. Rep. 8:3970-3970(2018).
CC   -!- FUNCTION: RNA-directed RNA polymerase that catalyzes the transcription
CC       of viral mRNAs, their capping and polyadenylation. The template is
CC       composed of the viral RNA tightly encapsidated by the nucleoprotein
CC       (N). The viral polymerase binds to the genomic RNA at the 3' leader
CC       promoter, and transcribes subsequently all viral mRNAs with a
CC       decreasing efficiency. The first gene is the most transcribed, and the
CC       last the least transcribed. The viral phosphoprotein acts as a
CC       processivity factor. Capping is concommitant with initiation of mRNA
CC       transcription. Indeed, a GDP polyribonucleotidyl transferase (PRNTase)
CC       adds the cap structure when the nascent RNA chain length has reached
CC       few nucleotides. Ribose 2'-O methylation of viral mRNA cap precedes and
CC       facilitates subsequent guanine-N-7 methylation, both activities being
CC       carried by the viral polymerase. Polyadenylation of mRNAs occur by a
CC       stuttering mechanism at a slipery stop site present at the end viral
CC       genes. After finishing transcription of a mRNA, the polymerase can
CC       resume transcription of the downstream gene.
CC       {ECO:0000250|UniProtKB:P03523, ECO:0000269|PubMed:23582637,
CC       ECO:0000269|PubMed:28991917, ECO:0000269|PubMed:29507309}.
CC   -!- FUNCTION: RNA-directed RNA polymerase that catalyzes the replication of
CC       viral genomic RNA. The template is composed of the viral RNA tightly
CC       encapsidated by the nucleoprotein (N). The replicase mode is dependent
CC       on intracellular N protein concentration. In this mode, the polymerase
CC       replicates the whole viral genome without recognizing transcriptional
CC       signals, and the replicated genome is not caped or polyadenylated.
CC       {ECO:0000250|UniProtKB:P03523, ECO:0000269|PubMed:23582637,
CC       ECO:0000269|PubMed:28991917, ECO:0000269|PubMed:29507309}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate +
CC         RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:14527, Rhea:RHEA-
CC         COMP:17342, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:140395;
CC         EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-ProRule:PRU00539};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 5'-end (5'-triphosphoguanosine)-adenylyl-adenylyl-cytidylyl-
CC         adenosine in mRNA + 2 S-adenosyl-L-methionine = a 5'-end (N(7)-methyl
CC         5'-triphosphoguanosine)-(2'-O-methyladenylyl)-adenylyl-cytidylyl-
CC         adenosine in mRNA + H(+) + 2 S-adenosyl-L-homocysteine;
CC         Xref=Rhea:RHEA:65376, Rhea:RHEA-COMP:16797, Rhea:RHEA-COMP:16798,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC         ChEBI:CHEBI:156483, ChEBI:CHEBI:156484; EC=2.1.1.375;
CC         Evidence={ECO:0000250|UniProtKB:P03523};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 5'-end (5'-triphosphoguanosine)-adenylyl-adenylyl-cytidylyl-
CC         adenosine in mRNA + S-adenosyl-L-methionine = a 5'-end (5'-
CC         triphosphoguanosine)-(2'-O-methyladenylyl)-adenylyl-cytidylyl-
CC         adenosine in mRNA + H(+) + S-adenosyl-L-homocysteine;
CC         Xref=Rhea:RHEA:65380, Rhea:RHEA-COMP:16797, Rhea:RHEA-COMP:16801,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC         ChEBI:CHEBI:156482, ChEBI:CHEBI:156484;
CC         Evidence={ECO:0000250|UniProtKB:P03523};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 5'-end triphospho-adenylyl-adenylyl-cytidylyl-adenosine in
CC         mRNA + GDP + H(+) = a 5'-end (5'-triphosphoguanosine)-adenylyl-
CC         adenylyl-cytidylyl-adenosine in mRNA + diphosphate;
CC         Xref=Rhea:RHEA:65436, Rhea:RHEA-COMP:16797, Rhea:RHEA-COMP:16799,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:33019, ChEBI:CHEBI:58189,
CC         ChEBI:CHEBI:156484, ChEBI:CHEBI:156503; EC=2.7.7.88;
CC         Evidence={ECO:0000250|UniProtKB:P28887};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 5'-end (5'-triphosphoguanosine)-(2'-O-methyladenylyl)-
CC         adenylyl-cytidylyl-adenosine in mRNA + S-adenosyl-L-methionine = a
CC         5'-end (N(7)-methyl 5'-triphosphoguanosine)-(2'-O-methyladenylyl)-
CC         adenylyl-cytidylyl-adenosine in mRNA + S-adenosyl-L-homocysteine;
CC         Xref=Rhea:RHEA:65440, Rhea:RHEA-COMP:16798, Rhea:RHEA-COMP:16801,
CC         ChEBI:CHEBI:57856, ChEBI:CHEBI:59789, ChEBI:CHEBI:156482,
CC         ChEBI:CHEBI:156483; Evidence={ECO:0000250|UniProtKB:P03523};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=GTP + H2O = GDP + H(+) + phosphate; Xref=Rhea:RHEA:19669,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565,
CC         ChEBI:CHEBI:43474, ChEBI:CHEBI:58189;
CC         Evidence={ECO:0000250|UniProtKB:P28887};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000269|PubMed:29507309};
CC   -!- SUBUNIT: Forms homooligomers. Interacts with VP35; this complex
CC       constitutes a functional polymerase complex.
CC       {ECO:0000269|PubMed:23582637}.
CC   -!- SUBCELLULAR LOCATION: Virion. Host cytoplasm
CC       {ECO:0000269|PubMed:23582637, ECO:0000269|PubMed:28991917}. Note=Found
CC       in cytoplasmic inclusion bodies present in infected cells.
CC       {ECO:0000269|PubMed:23582637, ECO:0000269|PubMed:28991917}.
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DR   EMBL; X67110; CAA47483.1; -; Genomic_RNA.
DR   EMBL; AF272001; AAG40171.1; -; Genomic_RNA.
DR   EMBL; AF086833; AAD14589.1; -; Genomic_RNA.
DR   EMBL; L11365; AAB81007.1; -; Genomic_RNA.
DR   EMBL; AY142960; AAN37511.1; -; Genomic_RNA.
DR   EMBL; AF499101; AAM76038.1; -; Genomic_RNA.
DR   RefSeq; NP_066251.1; NC_002549.1.
DR   SMR; Q05318; -.
DR   IntAct; Q05318; 1.
DR   ChEMBL; CHEMBL4303062; -.
DR   DrugBank; DB11676; Galidesivir.
DR   DrugBank; DB15686; GS-441524.
DR   DrugBank; DB14761; Remdesivir.
DR   GeneID; 911824; -.
DR   KEGG; vg:911824; -.
DR   Proteomes; UP000007209; Genome.
DR   Proteomes; UP000109874; Genome.
DR   Proteomes; UP000149419; Genome.
DR   Proteomes; UP000150973; Genome.
DR   GO; GO:0030430; C:host cell cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0044423; C:virion component; IEA:UniProtKB-KW.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0003924; F:GTPase activity; IEA:RHEA.
DR   GO; GO:0004482; F:mRNA 5'-cap (guanine-N7-)-methyltransferase activity; IEA:InterPro.
DR   GO; GO:0097747; F:RNA polymerase activity; IEP:DisProt.
DR   GO; GO:0003968; F:RNA-dependent RNA polymerase activity; IEA:UniProtKB-KW.
DR   GO; GO:0039689; P:negative stranded viral RNA replication; IDA:UniProtKB.
DR   GO; GO:0039697; P:negative stranded viral RNA transcription; IDA:UniProtKB.
DR   Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 1.
DR   InterPro; IPR039736; L_poly_C.
DR   InterPro; IPR026890; Mononeg_mRNAcap.
DR   InterPro; IPR014023; Mononeg_RNA_pol_cat.
DR   InterPro; IPR025786; Mononega_L_MeTrfase.
DR   InterPro; IPR017235; RNA-dir_pol_L_filovirus.
DR   InterPro; IPR029063; SAM-dependent_MTases_sf.
DR   NCBIfam; TIGR04198; paramyx_RNAcap; 2.
DR   Pfam; PF14318; Mononeg_mRNAcap; 1.
DR   Pfam; PF00946; Mononeg_RNA_pol; 1.
DR   PIRSF; PIRSF037548; RNA_pol_Filoviridae; 1.
DR   PROSITE; PS50526; RDRP_SSRNA_NEG_NONSEG; 1.
DR   PROSITE; PS51590; SAM_MT_MNV_L; 1.
PE   1: Evidence at protein level;
KW   ATP-binding; Host cytoplasm; Hydrolase; Methyltransferase; mRNA capping;
KW   mRNA processing; Multifunctional enzyme; Nucleotide-binding;
KW   Nucleotidyltransferase; Reference proteome; RNA-directed RNA polymerase;
KW   S-adenosyl-L-methionine; Transferase; Viral RNA replication; Virion.
FT   CHAIN           1..2212
FT                   /note="RNA-directed RNA polymerase L"
FT                   /id="PRO_0000222167"
FT   DOMAIN          625..809
FT                   /note="RdRp catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
FT   DOMAIN          1805..2003
FT                   /note="Mononegavirus-type SAM-dependent 2'-O-MTase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00923"
FT   REGION          1..450
FT                   /note="Homooligomerization"
FT                   /evidence="ECO:0000269|PubMed:23582637"
FT   REGION          1..380
FT                   /note="Interaction with VP35"
FT                   /evidence="ECO:0000269|PubMed:23582637"
FT   REGION          1653..1689
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           741..744
FT                   /note="Essential for both viral transcription and
FT                   replication"
FT                   /evidence="ECO:0000269|PubMed:28991917"
FT   COMPBIAS        1655..1673
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1674..1688
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   VARIANT         820
FT                   /note="T -> A"
FT   VARIANT         934
FT                   /note="F -> L"
FT   VARIANT         1532
FT                   /note="I -> V"
FT   MUTAGEN         742..744
FT                   /note="DNQ->AAA: Complete loss of replication and
FT                   transcription."
FT                   /evidence="ECO:0000269|PubMed:28991917"
FT   MUTAGEN         742
FT                   /note="D->A: Complete loss OFRNA synthesis."
FT                   /evidence="ECO:0000269|PubMed:29507309"
SQ   SEQUENCE   2212 AA;  252724 MW;  5B07EDDC370E2934 CRC64;
     MATQHTQYPD ARLSSPIVLD QCDLVTRACG LYSSYSLNPQ LRNCKLPKHI YRLKYDVTVT
     KFLSDVPVAT LPIDFIVPVL LKALSGNGFC PVEPRCQQFL DEIIKYTMQD ALFLKYYLKN
     VGAQEDCVDE HFQEKILSSI QGNEFLHQMF FWYDLAILTR RGRLNRGNSR STWFVHDDLI
     DILGYGDYVF WKIPISMLPL NTQGIPHAAM DWYQASVFKE AVQGHTHIVS VSTADVLIMC
     KDLITCRFNT TLISKIAEIE DPVCSDYPNF KIVSMLYQSG DYLLSILGSD GYKIIKFLEP
     LCLAKIQLCS KYTERKGRFL TQMHLAVNHT LEEITEMRAL KPSQAQKIRE FHRTLIRLEM
     TPQQLCELFS IQKHWGHPVL HSETAIQKVK KHATVLKALR PIVIFETYCV FKYSIAKHYF
     DSQGSWYSVT SDRNLTPGLN SYIKRNQFPP LPMIKELLWE FYHLDHPPLF STKIISDLSI
     FIKDRATAVE RTCWDAVFEP NVLGYNPPHK FSTKRVPEQF LEQENFSIEN VLSYAQKLEY
     LLPQYRNFSF SLKEKELNVG RTFGKLPYPT RNVQTLCEAL LADGLAKAFP SNMMVVTERE
     QKESLLHQAS WHHTSDDFGE HATVRGSSFV TDLEKYNLAF RYEFTAPFIE YCNRCYGVKN
     VFNWMHYTIP QCYMHVSDYY NPPHNLTLEN RDNPPEGPSS YRGHMGGIEG LQQKLWTSIS
     CAQISLVEIK TGFKLRSAVM GDNQCITVLS VFPLETDADE QEQSAEDNAA RVAASLAKVT
     SACGIFLKPD ETFVHSGFIY FGKKQYLNGV QLPQSLKTAT RMAPLSDAIF DDLQGTLASI
     GTAFERSISE TRHIFPCRIT AAFHTFFSVR ILQYHHLGFN KGFDLGQLTL GKPLDFGTIS
     LALAVPQVLG GLSFLNPEKC FYRNLGDPVT SGLFQLKTYL RMIEMDDLFL PLIAKNPGNC
     TAIDFVLNPS GLNVPGSQDL TSFLRQIVRR TITLSAKNKL INTLFHASAD FEDEMVCKWL
     LSSTPVMSRF AADIFSRTPS GKRLQILGYL EGTRTLLASK IINNNTETPV LDRLRKITLQ
     RWSLWFSYLD HCDNILAEAL TQITCTVDLA QILREYSWAH ILEGRPLIGA TLPCMIEQFK
     VFWLKPYEQC PQCSNAKQPG GKPFVSVAVK KHIVSAWPNA SRISWTIGDG IPYIGSRTED
     KIGQPAIKPK CPSAALREAI ELASRLTWVT QGSSNSDLLI KPFLEARVNL SVQEILQMTP
     SHYSGNIVHR YNDQYSPHSF MANRMSNSAT RLIVSTNTLG EFSGGGQSAR DSNIIFQNVI
     NYAVALFDIK FRNTEATDIQ YNRAHLHLTK CCTREVPAQY LTYTSTLDLD LTRYRENELI
     YDSNPLKGGL NCNISFDNPF FQGKRLNIIE DDLIRLPHLS GWELAKTIMQ SIISDSNNSS
     TDPISSGETR SFTTHFLTYP KIGLLYSFGA FVSYYLGNTI LRTKKLTLDN FLYYLTTQIH
     NLPHRSLRIL KPTFKHASVM SRLMSIDPHF SIYIGGAAGD RGLSDAARLF LRTSISSFLT
     FVKEWIINRG TIVPLWIVYP LEGQNPTPVN NFLYQIVELL VHDSSRQQAF KTTISDHVHP
     HDNLVYTCKS TASNFFHASL AYWRSRHRNS NRKYLARDSS TGSSTNNSDG HIERSQEQTT
     RDPHDGTERN LVLQMSHEIK RTTIPQENTH QGPSFQSFLS DSACGTANPK LNFDRSRHNV
     KFQDHNSASK REGHQIISHR LVLPFFTLSQ GTRQLTSSNE SQTQDEISKY LRQLRSVIDT
     TVYCRFTGIV SSMHYKLDEV LWEIESFKSA VTLAEGEGAG ALLLIQKYQV KTLFFNTLAT
     ESSIESEIVS GMTTPRMLLP VMSKFHNDQI EIILNNSASQ ITDITNPTWF KDQRARLPKQ
     VEVITMDAET TENINRSKLY EAVYKLILHH IDPSVLKAVV LKVFLSDTEG MLWLNDNLAP
     FFATGYLIKP ITSSARSSEW YLCLTNFLST TRKMPHQNHL SCKQVILTAL QLQIQRSPYW
     LSHLTQYADC ELHLSYIRLG FPSLEKVLYH RYNLVDSKRG PLVSITQHLA HLRAEIRELT
     NDYNQQRQSR TQTYHFIRTA KGRITKLVND YLKFFLIVQA LKHNGTWQAE FKKLPELISV
     CNRFYHIRDC NCEERFLVQT LYLHRMQDSE VKLIERLTGL LSLFPDGLYR FD
//