ID   RIR1_HHV23              Reviewed;        1144 AA.
AC   P09853;
DT   01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1996, sequence version 2.
DT   24-JAN-2024, entry version 111.
DE   RecName: Full=Ribonucleoside-diphosphate reductase large subunit {ECO:0000255|HAMAP-Rule:MF_04026};
DE            Short=R1 {ECO:0000255|HAMAP-Rule:MF_04026};
DE            EC=1.17.4.1 {ECO:0000255|HAMAP-Rule:MF_04026};
DE   AltName: Full=Ribonucleotide reductase large subunit {ECO:0000255|HAMAP-Rule:MF_04026};
GN   Name=RIR1 {ECO:0000255|HAMAP-Rule:MF_04026};
OS   Human herpesvirus 2 (strain 333) (HHV-2) (Human herpes simplex virus 2).
OC   Viruses; Duplodnaviria; Heunggongvirae; Peploviricota; Herviviricetes;
OC   Herpesvirales; Orthoherpesviridae; Alphaherpesvirinae; Simplexvirus;
OC   Simplexvirus humanalpha2; Human herpesvirus 2.
OX   NCBI_TaxID=10313;
OH   NCBI_TaxID=9606; Homo sapiens (Human).
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=2419588; DOI=10.1128/jvi.57.3.802-808.1986;
RA   Swain M.A., Galloway D.A.;
RT   "Herpes simplex virus specifies two subunits of ribonucleotide reductase
RT   encoded by 3'-coterminal transcripts.";
RL   J. Virol. 57:802-808(1986).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 981-1144.
RX   PubMed=6321759; DOI=10.1128/jvi.49.3.724-730.1984;
RA   Galloway D.A., Swain M.A.;
RT   "Organization of the left-hand end of the herpes simplex virus type 2 BglII
RT   N fragment.";
RL   J. Virol. 49:724-730(1984).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1036-1144.
RX   PubMed=6315408; DOI=10.1002/j.1460-2075.1983.tb01684.x;
RA   McLauchlan J., Clements J.B.;
RT   "DNA sequence homology between two co-linear loci on the HSV genome which
RT   have different transforming abilities.";
RL   EMBO J. 2:1953-1961(1983).
RN   [4]
RP   REVIEW.
RX   PubMed=18990579; DOI=10.1016/j.tibs.2008.09.008;
RA   Lembo D., Brune W.;
RT   "Tinkering with a viral ribonucleotide reductase.";
RL   Trends Biochem. Sci. 34:25-32(2009).
CC   -!- FUNCTION: Ribonucleoside-diphosphate reductase holoenzyme that provides
CC       the precursors necessary for viral DNA synthesis. Allows virus growth
CC       in non-dividing cells, as well as reactivation from latency in infected
CC       hosts. Catalyzes the biosynthesis of deoxyribonucleotides from the
CC       corresponding ribonucleotides (By similarity). The N-terminal region
CC       confers antiapoptotic activity in differentiated cells such as neurons
CC       and is important for viral reactivation to increase neural
CC       survivability. Prevents host necroptosis by targeting host RIPK1 and
CC       RIPK3, thereby hampering the formation of necroptotic RIPK1-RIPK3
CC       complexes (By similarity). May form hetero-amyloid structures with host
CC       proteins RIPK3 or ZBP1, thereby preventing RIPK3- and ZBP1-mediated
CC       necroptosis (By similarity). In addition, inhibits extrinsic apoptosis
CC       by targeting host CASP8 (By similarity). {ECO:0000250|UniProtKB:P08543,
CC       ECO:0000250|UniProtKB:P89462, ECO:0000255|HAMAP-Rule:MF_04026}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=[thioredoxin]-disulfide + a 2'-deoxyribonucleoside 5'-
CC         diphosphate + H2O = [thioredoxin]-dithiol + a ribonucleoside 5'-
CC         diphosphate; Xref=Rhea:RHEA:23252, Rhea:RHEA-COMP:10698, Rhea:RHEA-
CC         COMP:10700, ChEBI:CHEBI:15377, ChEBI:CHEBI:29950, ChEBI:CHEBI:50058,
CC         ChEBI:CHEBI:57930, ChEBI:CHEBI:73316; EC=1.17.4.1;
CC         Evidence={ECO:0000255|HAMAP-Rule:MF_04026};
CC   -!- SUBUNIT: Heterotetramer composed of a homodimer of the large subunit
CC       (R1) and a homodimer of the small subunit (R2). Larger multisubunit
CC       protein complex are also active, composed of (R1)n(R2)n (By
CC       similarity). May self-assemble (via RIP homotypic interaction
CC       motif/RHIM) into homomeric fibrillar amyloid structures (By
CC       similarity). Interacts (via RHIM) with human RIPK1 (via RHIM).
CC       Interacts (via RHIM) with human RIPK3 (via RHIM) (By similarity). May
CC       interact (via RHIM) with human ZBP1 (via RHIM) (By similarity).
CC       Interacts (via C-terminus) with host CASP8 (By similarity).
CC       {ECO:0000250|UniProtKB:P08543, ECO:0000250|UniProtKB:P89462,
CC       ECO:0000255|HAMAP-Rule:MF_04026}.
CC   -!- DOMAIN: The RIP homotypic interaction motif/RHIM may drive self-
CC       assembly into homomeric amyloid structures and mediates interaction
CC       with the RHIM motif of host proteins RIPK3 and ZBP1 to form heteromeric
CC       amyloid structures. {ECO:0000250|UniProtKB:P08543}.
CC   -!- SIMILARITY: Belongs to the ribonucleoside diphosphate reductase large
CC       chain family. {ECO:0000255|HAMAP-Rule:MF_04026}.
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DR   EMBL; M12700; AAA45806.1; -; Genomic_DNA.
DR   EMBL; X00048; CAA24929.1; -; Genomic_DNA.
DR   SMR; P09853; -.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-UniRule.
DR   GO; GO:0004748; F:ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor; IEA:UniProtKB-UniRule.
DR   GO; GO:0006260; P:DNA replication; IEA:UniProtKB-UniRule.
DR   GO; GO:0039526; P:perturbation by virus of host apoptosis; IEA:UniProtKB-KW.
DR   GO; GO:0019046; P:release from viral latency; IEA:UniProtKB-KW.
DR   GO; GO:0019050; P:suppression by virus of host apoptotic process; IEA:UniProtKB-KW.
DR   Gene3D; 3.20.70.20; -; 1.
DR   HAMAP; MF_04026; HSV_RIR1; 1.
DR   InterPro; IPR034717; HSV_RIR1.
DR   InterPro; IPR013346; NrdE_NrdA_C.
DR   InterPro; IPR000788; RNR_lg_C.
DR   InterPro; IPR013509; RNR_lsu_N.
DR   InterPro; IPR039718; Rrm1.
DR   NCBIfam; TIGR02506; NrdE_NrdA; 1.
DR   PANTHER; PTHR11573; RIBONUCLEOSIDE-DIPHOSPHATE REDUCTASE LARGE CHAIN; 1.
DR   PANTHER; PTHR11573:SF6; RIBONUCLEOSIDE-DIPHOSPHATE REDUCTASE LARGE SUBUNIT; 1.
DR   Pfam; PF02867; Ribonuc_red_lgC; 1.
DR   Pfam; PF00317; Ribonuc_red_lgN; 1.
DR   PRINTS; PR01183; RIBORDTASEM1.
DR   SUPFAM; SSF51998; PFL-like glycyl radical enzymes; 1.
DR   PROSITE; PS00089; RIBORED_LARGE; 1.
PE   3: Inferred from homology;
KW   ATP-binding; Disulfide bond; DNA replication; Early protein;
KW   Host-virus interaction; Inhibition of host caspases by virus;
KW   Modulation of host cell apoptosis by virus; Nucleotide-binding;
KW   Oxidoreductase; Viral latency; Viral reactivation from latency.
FT   CHAIN           1..1144
FT                   /note="Ribonucleoside-diphosphate reductase large subunit"
FT                   /id="PRO_0000187237"
FT   REGION          1..33
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          118..324
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           55..75
FT                   /note="RIP homotypic interaction motif (RHIM)"
FT                   /evidence="ECO:0000250|UniProtKB:P08543"
FT   COMPBIAS        118..136
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        144..161
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        189..203
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        204..221
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        798
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   ACT_SITE        800
FT                   /note="Cysteine radical intermediate"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   ACT_SITE        802
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   BINDING         573
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   BINDING         588..589
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   BINDING         619
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   BINDING         798..802
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   BINDING         975..979
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   SITE            589
FT                   /note="Important for hydrogen atom transfer"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   SITE            815
FT                   /note="Important for hydrogen atom transfer"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   SITE            1118
FT                   /note="Important for electron transfer"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   SITE            1119
FT                   /note="Important for electron transfer"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   SITE            1139
FT                   /note="Interacts with thioredoxin/glutaredoxin"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   SITE            1142
FT                   /note="Interacts with thioredoxin/glutaredoxin"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
FT   DISULFID        589..815
FT                   /note="Redox-active"
FT                   /evidence="ECO:0000255|HAMAP-Rule:MF_04026"
SQ   SEQUENCE   1144 AA;  125093 MW;  4771481C3103FC78 CRC64;
     MANRPAASAL AGARSPSERQ EPREPEVAPP GGDHVFCRKV SGVMVLSSDP PGPAAYRISD
     SSFVQCGSNC SMIIDGDVAR GHLRDLEGAT STGAFVAISN VAAGGDGRTA VVALGGTSGP
     SATTSVGTQT SGEFLHGNPR TPEPQGPQAV PPPPPPPFPW GHECCARRDA RGGAEKDVGA
     AESWSDGPSS DSETEDSDSS DEDTGSGSET LSRSSSIWAA GATDDDDSDS DSRSDDSVQP
     DVVVRRRWSD GPAPVAFPKP RRPGDSPGNP GLGAGTGPGS ATDPRASADS DSAAHAAAPQ
     ADVAPVLDSQ PTVGTDPGYP VPLELTPENA EAVARFLGDA VDREPALMLE YFCRCAREES
     KRVPPRTFGS APRLTEDDFG LLNYALAEMR RLCLDLPPVP PNAYTPYHLR EYATRLVNGF
     KPLVRRSARL YRILGILVHL RIRTREASFE EWMRSKEVDL DFGLTERLRE HEAQLMILAQ
     ALNPYDCLIH STPNTLVERG LQSALKYEEF YLKRFGGHYM ESVFQMYTRI AGFLACRATR
     GMRHIALGRQ GSWWEMFKFF FHRLYDHQIV PSTPAMLNLG TRNYYTSSCY LVNPQATTNQ
     ATLRAITGNV SAILARNGGI GLCMQAFNDA SPGTASIMPA LKVLDSLVAA HNKQSTRPTG
     ACVYLEPWHS DVRAVLRMKG VLAGEEAQRC DNIFSALWMP DLFFKRLIRH LDGEKNVTWS
     LFDRDTSMSL ADFHGEEFEK LYEHLEAMGF GETIPIQDLA YAIVRSAATT GSPFIMFKDA
     VNRHYIYDTQ GAAIAGSNLC TEIVHPSSKR SSGVCNLGSV NLARCVSRRT FDFGMLRDAV
     QACVLMVNIM IDSTLQPTPQ CARGHDNLRS MGIGMQGLHT ACLKMGLDLE SAEFRDLNTH
     IAEVMLLAAM KTSNALCVRG ARPFSHFKRS MYRAGRFHWE RFSNASPRYE GEWEMLRQSM
     MKHGLRNSQF IALMPTAASA QISDVSEGFA PLFTNLFSKV TRDGETLRPN TLLLKELERT
     FGGKRLLDAM DGLEAKQWSV AQALPCLDPA HPLRRFKTAF DYDQELLIDL CADRAPYVDH
     SQSMTLYVTE KADGTLPAST LVRLLVHAYK RGLKTGMYYC KVRKATNSGV FAGDDNIVCT
     SCAL
//