ID   L_HANTV                 Reviewed;        2151 AA.
AC   P23456;
DT   01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1996, sequence version 3.
DT   08-NOV-2023, entry version 93.
DE   RecName: Full=RNA-directed RNA polymerase L;
DE            Short=Protein L;
DE            EC=2.7.7.48;
DE   AltName: Full=Large structural protein;
DE   AltName: Full=RdRp {ECO:0000305};
DE   AltName: Full=Replicase;
DE   AltName: Full=Transcriptase;
DE   Includes:
DE     RecName: Full=cap-snatching endonuclease;
DE              EC=3.1.-.- {ECO:0000269|PubMed:27304209};
GN   Name=L;
OS   Hantaan virus (strain 76-118) (Korean hemorrhagic fever virus).
OC   Viruses; Riboviria; Orthornavirae; Negarnaviricota; Polyploviricotina;
OC   Ellioviricetes; Bunyavirales; Hantaviridae; Mammantavirinae;
OC   Orthohantavirus; Orthohantavirus hantanense.
OX   NCBI_TaxID=11602;
OH   NCBI_TaxID=39030; Apodemus agrarius (Eurasian field mouse).
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC RNA].
RX   PubMed=2123544; DOI=10.1093/nar/18.22.6728;
RA   Schmaljohn C.S.;
RT   "Nucleotide sequence of the L genome segment of Hantaan virus.";
RL   Nucleic Acids Res. 18:6728-6728(1990).
RN   [2]
RP   SEQUENCE REVISION.
RX   PubMed=1626424; DOI=10.1016/0168-1702(92)90029-9;
RA   Antic D., Kang C.Y., Spik K., Schmaljohn C.S., Vapalahti O., Vaheri A.;
RT   "Comparison of the deduced gene products of the L, M and S genome segments
RT   of hantaviruses.";
RL   Virus Res. 24:35-46(1992).
RN   [3]
RP   SEQUENCE REVISION TO 353-354; 916 AND 1953.
RA   Schmaljohn C.S.;
RL   Submitted (JUN-1994) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   REVIEW.
RX   PubMed=15503219; DOI=10.1007/s00705-004-0414-8;
RA   Kukkonen S.K., Vaheri A., Plyusnin A.;
RT   "L protein, the RNA-dependent RNA polymerase of hantaviruses.";
RL   Arch. Virol. 150:533-556(2005).
RN   [5]
RP   REVIEW.
RX   PubMed=28418734; DOI=10.1080/1040841x.2017.1307805;
RA   Amroun A., Priet S., de Lamballerie X., Querat G.;
RT   "Bunyaviridae RdRps: structure, motifs, and RNA synthesis machinery.";
RL   Crit. Rev. Microbiol. 43:753-778(2017).
RN   [6]
RP   REVIEW.
RX   PubMed=31948728; DOI=10.1016/j.tim.2019.12.006;
RA   Olschewski S., Cusack S., Rosenthal M.;
RT   "The Cap-Snatching Mechanism of Bunyaviruses.";
RL   Trends Microbiol. 28:293-303(2020).
RN   [7] {ECO:0007744|PDB:5IZE}
RP   X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 1-179 IN COMPLEX WITH MANGANESE,
RP   FUNCTION, CATALYTIC ACTIVITY, COFACTOR, MUTAGENESIS OF HIS-36; GLU-54;
RP   ASP-97; LYS-124 AND LYS-127, AND ACTIVITY REGULATION.
RX   PubMed=27304209; DOI=10.1371/journal.ppat.1005636;
RA   Reguera J., Gerlach P., Rosenthal M., Gaudon S., Coscia F., Guenther S.,
RA   Cusack S.;
RT   "Comparative Structural and Functional Analysis of Bunyavirus and
RT   Arenavirus Cap-Snatching Endonucleases.";
RL   PLoS Pathog. 12:e1005636-e1005636(2016).
CC   -!- FUNCTION: RNA-dependent RNA polymerase, which is responsible for the
CC       replication and transcription of the viral RNA genome using antigenomic
CC       RNA as an intermediate (By similarity). During transcription,
CC       synthesizes subgenomic RNAs and assures their capping by a cap-
CC       snatching mechanism, which involves the endonuclease activity cleaving
CC       the host capped pre-mRNAs (PubMed:27304209). These short capped RNAs
CC       are then used as primers for viral transcription. Cleaves ssRNA
CC       substrates but not DNA (By similarity). Seems to downregulate the
CC       expression of its own and heterologous mRNAs through its endonuclease
CC       activity (By similarity). {ECO:0000250|UniProtKB:Q9E005,
CC       ECO:0000269|PubMed:27304209}.
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         ECO:0000269|PubMed:27304209};
CC   -!- COFACTOR:
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC         Evidence={ECO:0000269|PubMed:27304209};
CC       Note=For endonuclease activity. Binds 2 Mn(2+) ions in the active site
CC       (PubMed:27304209). Displays nuclease activity with Mn(2+) and also some
CC       with Co(2+), but not with Mg(2+), Ca(2+), Ni(2+), and Zn(2+)
CC       (PubMed:27304209). {ECO:0000269|PubMed:27304209};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC         Evidence={ECO:0000250|UniProtKB:A2SZS3};
CC       Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC         Evidence={ECO:0000250|UniProtKB:A2SZS3};
CC       Note=For polymerase activity. {ECO:0000250|UniProtKB:A2SZS3};
CC   -!- ACTIVITY REGULATION: Inhibited by 2,4-dioxo-4-phenylbutanoic acid
CC       (DPBA). {ECO:0000269|PubMed:27304209}.
CC   -!- SUBUNIT: Interacts with the viral nucleoprotein.
CC       {ECO:0000250|UniProtKB:Q89709}.
CC   -!- SUBCELLULAR LOCATION: Host cytoplasm, host perinuclear region
CC       {ECO:0000250|UniProtKB:Q9YQR5}.
CC   -!- DOMAIN: The N-terminus contains the endonuclease activity (endoN) (By
CC       similarity). The central region contains the RdRp activity (By
CC       similarity). The C-terminus contains the cap-binding region (By
CC       similarity). {ECO:0000250|UniProtKB:A2SZS3,
CC       ECO:0000250|UniProtKB:I0DF35, ECO:0000250|UniProtKB:Q9E005}.
CC   -!- MISCELLANEOUS: Classified as His(+) endonuclease since it has a
CC       histidine upstream of the active site that coordinates the first
CC       cation. {ECO:0000303|PubMed:31948728}.
CC   -!- SIMILARITY: Belongs to the Bunyavirales RNA polymerase family.
CC       {ECO:0000305}.
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DR   EMBL; X55901; CAA39394.1; -; Genomic_RNA.
DR   PIR; S13553; S13553.
DR   PDB; 5IZE; X-ray; 1.70 A; A/B=1-179.
DR   PDB; 8C4S; EM; 3.27 A; A=1-2151.
DR   PDB; 8C4T; EM; 3.23 A; A=1-2151.
DR   PDB; 8C4U; EM; 3.36 A; A=1-2151.
DR   PDB; 8C4V; EM; 3.14 A; A=1-2151.
DR   PDBsum; 5IZE; -.
DR   PDBsum; 8C4S; -.
DR   PDBsum; 8C4T; -.
DR   PDBsum; 8C4U; -.
DR   PDBsum; 8C4V; -.
DR   SMR; P23456; -.
DR   Proteomes; UP000008627; Genome.
DR   GO; GO:0044220; C:host cell perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:0004519; F:endonuclease activity; IMP:UniProtKB.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR   GO; GO:0003968; F:RNA-dependent RNA polymerase activity; IEA:UniProtKB-KW.
DR   GO; GO:0075526; P:cap snatching; IMP:UniProtKB.
DR   GO; GO:0006351; P:DNA-templated transcription; IEA:InterPro.
DR   GO; GO:0039689; P:negative stranded viral RNA replication; ISS:UniProtKB.
DR   GO; GO:0039696; P:RNA-templated viral transcription; ISS:UniProtKB.
DR   InterPro; IPR048006; CapSnatch_bunyavir.
DR   InterPro; IPR016268; RNA-dir_pol_hantavirus.
DR   InterPro; IPR024378; RNA-dir_pol_N_hantavirus.
DR   InterPro; IPR007099; RNA-dir_pol_NSvirus.
DR   InterPro; IPR007322; RNA_pol_bunyavir.
DR   NCBIfam; TIGR04202; capSnatchArena; 1.
DR   Pfam; PF04196; Bunya_RdRp; 1.
DR   Pfam; PF12426; DUF3674; 1.
DR   PIRSF; PIRSF000825; L_HantaV; 1.
DR   PROSITE; PS50525; RDRP_SSRNA_NEG_SEG; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Cap snatching; Endonuclease; Host cytoplasm; Hydrolase;
KW   Magnesium; Manganese; Metal-binding; Nuclease; Nucleotide-binding;
KW   Nucleotidyltransferase; Reference proteome; RNA-directed RNA polymerase;
KW   Transferase; Viral RNA replication.
FT   CHAIN           1..2151
FT                   /note="RNA-directed RNA polymerase L"
FT                   /id="PRO_0000222021"
FT   DOMAIN          956..1142
FT                   /note="RdRp catalytic"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00539"
FT   ACT_SITE        124
FT                   /note="For endonuclease activity"
FT                   /evidence="ECO:0000305|PubMed:27304209"
FT   BINDING         36
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000269|PubMed:27304209"
FT   BINDING         54
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000269|PubMed:27304209"
FT   BINDING         97
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000269|PubMed:27304209"
FT   BINDING         97
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="2"
FT                   /evidence="ECO:0000269|PubMed:27304209"
FT   BINDING         110
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000269|PubMed:27304209"
FT   BINDING         111
FT                   /ligand="Mn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29035"
FT                   /ligand_label="1"
FT                   /evidence="ECO:0000269|PubMed:27304209"
FT   BINDING         1099
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /ligand_note="catalytic; for RdRp activity"
FT                   /evidence="ECO:0000250|UniProtKB:I0DF35"
FT   MUTAGEN         36
FT                   /note="H->A: Complete loss of cap-snatching endonuclease
FT                   activity."
FT                   /evidence="ECO:0000269|PubMed:27304209"
FT   MUTAGEN         54
FT                   /note="E->G: Loss of binding to 1 Mn(2+) ion. Complete loss
FT                   of cap-snatching endonuclease activity."
FT                   /evidence="ECO:0000269|PubMed:27304209"
FT   MUTAGEN         97
FT                   /note="D->A: Loss of binding to 2 Mn(2+) ions. Complete
FT                   loss of cap-snatching endonuclease activity."
FT                   /evidence="ECO:0000269|PubMed:27304209"
FT   MUTAGEN         124
FT                   /note="K->A: Complete loss of cap-snatching endonuclease
FT                   activity."
FT                   /evidence="ECO:0000269|PubMed:27304209"
FT   MUTAGEN         127
FT                   /note="K->A: Severe loss of cap-snatching endonuclease
FT                   activity."
FT                   /evidence="ECO:0000269|PubMed:27304209"
FT   HELIX           1..11
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   HELIX           12..14
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   HELIX           21..46
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   STRAND          51..53
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   HELIX           57..63
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   HELIX           68..74
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   HELIX           88..91
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   STRAND          97..102
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   STRAND          105..115
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   HELIX           117..144
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   STRAND          147..150
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   STRAND          153..166
FT                   /evidence="ECO:0007829|PDB:5IZE"
FT   STRAND          168..171
FT                   /evidence="ECO:0007829|PDB:5IZE"
SQ   SEQUENCE   2151 AA;  246499 MW;  DBD2A901351DFE0B CRC64;
     MDKYREIHNK LKEFSPGTLT AVECIDYLDR LYAVRHDIVD QMIKHDWSDN KDSEEAIGKV
     LLFAGVPSNI ITALEKKIIP NHPTGKSLKA FFKMTPDNYK ISGTTIEFVE VTVTADVDKG
     IREKKLKYEA GLTYIEQELH KFFLKGEIPQ PYKITFNVVA VRTDGSNITT QWPSRRNDGV
     VQYMRLVQAE ISYVREHLIK TEERAALEAM FNLKFNISTH KSQPYYIPDY KGMEPIGANI
     EDLVDYSKDW LSRARNFSFF EVKGTAVFEC FNSNEANHCQ RYPMSRKPRN FLLIQCSLIT
     SYKPATTLSD QIDSRRACSY ILNLIPDTPA SYLIHDMAYR YINLTREDMI NYYAPRIQFK
     QTQNVREPGT FKLTSSMLRA ESKAMLDLLN NHKSGEKHGA QIESLNIASH IVQSESVSLI
     TKILSDLELN ITEPSTQEYS TTKHTYVDTV LDKFFQNETQ KYLIDVLKKT TAWHIGHLIR
     DITESLIAHS GLKRSKYWSL HSYNNGNVIL FILPSKSLEV AGSFIRFITV FRIGPGLVDK
     DNLDTILIDG DSQWGVSKVM SIDLNRLLAL NIAFEKALIA TATWFQYYTE DQGQFPLQYA
     IRSVFANHFL LAICQKMKLC AIFDNLRYLI PAVTSLYSGF PSLIEKLFER PFKSSLEVYI
     YYNIKSLLVA LAQNNKARFY SKVKLLGLTV DQSTVGASGV YPSFMSRIVY KHYRSLISEV
     TTCFFLFEKG LHGNMNEEAK IHLETVEWAL KFREKEEKYG ESLVENGYMM WELRANAELA
     EQQLYCQDAI ELAAIELNKV LATKSSVVAN SILSKNWEEP YFSQTRNISL KGMSGQVQED
     GHLSSSVTII EAIRYLSNSR HNPSLLKLYE ETREQKAMAR IVRKYQRTEA DRGFFITTLP
     TRCRLEIIED YYDAIAKNIS EEYISYGGEK KILAIQGALE KALRWASGES FIELSNHKFI
     RMKRKLMYVS ADATKWSPGD NSAKFRRFTS MLHNGLPNNK LKNCVIDALK QVYKTDFFMS
     RKLRNYIDSM ESLDPHIKQF LDFFPDGHHG EVKGNWLQGN LNKCSSLFGV AMSLLFKQVW
     TNLFPELDCF FEFAHHSDDA LFIYGYLEPV DDGTDWFLFV SQQIQAGHLH WFSVNTEMWK
     SMFNLHEHIL LLGSIKISPK KTTVSPTNAE FLSTFFEGCA VSIPFVKILL GSLSDLPGLG
     YFDDLAAAQS RCVKALDLGA SPQVAQLAVA LCTSKVERLY GTAPGMVNHP AAYLQVKHTD
     TPIPLGGNGA MSIMELATAG IGMSDKNLLK RALLGYSHKR QKSMLYILGL FKFLMKLSDE
     TFQHERLGQF SFIGKVQWKI FTPKSEFEFA DMYTSKFLEL WSSQHVTYDY IIPKGRDNLL
     IYLVRKLNDP SIVTAMTMQS PLQLRFRMQA KQHMKVCRLD GEWVTFREVL AAANSFAENY
     SATSQDMDLF QTLTSCTFSK EYAWKDFLNG IHCDVIPTKQ VQRAKVARTF TVREKDQIIQ
     NSIPAVIGYK FAVTVEEMSD VLDTAKFPDS LSVDLKTMKD GVYRELGLDI SLPDVMKRIA
     PMLYKSSKSR VVIVQGNVEG TAEAICRYWL KSMSLVKTIR VKPHKEVLQA VSIFNRKEDI
     GQQKDLAALK LCIEVWRWCK ANSAPYRDWF QALWFEDKTF SEWLDRFCRV GVPPIDPEIQ
     CAALMIADIK GDYSVLQLQA NRRAYSGKQY DAYCVQTYNE VTKLYEGDLR VTFNFGLDCA
     RLEIFWDKKA YILETSITQK HVLKIMMDEV SKELIKCGMR FNTEQVQGVR HMVLFKTESG
     FEWGKPNIPC IVYKNCVLRT SLRTTQAINH KFMITIKDDG LRAIAQHDED SPRFLLAHAF
     HTIRDIRYQA VDAVSNVWFI HKGVKLYLNP IISSGLLENF MKNLPAAIPP AAYSLIMNRA
     KISVDLFMFN DLLKLINPRN TLDLSGLETT GDEFSTVSSM SSRLWSEEMS LVDDDEELDD
     EFTIDLQDVD FENIDIEADI EHFLQDESSY TGDLLISTEE TESKKMRGIV KILEPVRLIK
     SWVSRGLSIE KVYSPVNIIL MSRYISKTFN LSTKQVSLLD PYDLTELESI VRGWGECVID
     QFESLDREAQ NMVVNKGICP EDVIPDSLFS FRHTMVLLRR LFPQDSISSF Y
//