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P23921 (RIR1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 148. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Ribonucleoside-diphosphate reductase large subunit

EC=1.17.4.1
Alternative name(s):
Ribonucleoside-diphosphate reductase subunit M1
Ribonucleotide reductase large subunit
Gene names
Name:RRM1
Synonyms:RR1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length792 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides.

Catalytic activity

2'-deoxyribonucleoside diphosphate + thioredoxin disulfide + H2O = ribonucleoside diphosphate + thioredoxin. Ref.8

Enzyme regulation

Under complex allosteric control mediated by deoxynucleoside triphosphates and ATP binding to separate specificity and activation sites on the M1 subunit. The type of nucleotide bound at the specificity site determines substrate preference. It seems probable that ATP makes the enzyme reduce CDP and UDP, dGTP favors ADP reduction and dTTP favors GDP reduction. Stimulated by ATP and inhibited by dATP binding to the activity site. Ref.6 Ref.8

Pathway

Genetic information processing; DNA replication.

Subunit structure

Heterodimer of a large and a small subunit. Heterodimer with small subunit RRM2 or RRM2B. The heterodimer with RRM2 has higher catalytic activity than the heterodimer with RRM2B. Ref.8

Subcellular location

Cytoplasm.

Miscellaneous

Two distinct regulatory sites have been defined: the specificity site, which controls substrate specificity, and the activity site which regulates overall catalytic activity. A substrate-binding catalytic site, located on M1, is formed only in the presence of the second subunit M2.

The level of the enzyme activity is closely correlated with the growth rate of a cell and appears to vary with the cell cycle.

Sequence similarities

Belongs to the ribonucleoside diphosphate reductase large chain family.

Contains 1 ATP-cone domain.

Ontologies

Keywords
   Biological processDNA replication
   Cellular componentCytoplasm
   Coding sequence diversityPolymorphism
   LigandATP-binding
Nucleotide-binding
   Molecular functionOxidoreductase
   PTMAcetylation
Disulfide bond
   Technical term3D-structure
Allosteric enzyme
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA replication

Inferred from electronic annotation. Source: UniProtKB-UniPathway

cell proliferation in forebrain

Inferred from electronic annotation. Source: Ensembl

deoxyribonucleotide biosynthetic process

Inferred from sequence or structural similarity. Source: UniProtKB

male gonad development

Inferred from electronic annotation. Source: Ensembl

mitotic cell cycle

Inferred from electronic annotation. Source: Ensembl

nucleobase-containing small molecule interconversion

Traceable author statement. Source: Reactome

nucleobase-containing small molecule metabolic process

Traceable author statement. Source: Reactome

protein heterotetramerization

Inferred from electronic annotation. Source: Ensembl

pyrimidine nucleobase metabolic process

Inferred from electronic annotation. Source: Ensembl

response to ionizing radiation

Inferred from electronic annotation. Source: Ensembl

retina development in camera-type eye

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

   Cellular_componentcell projection

Inferred from electronic annotation. Source: Ensembl

cytoplasm

Inferred from direct assay. Source: HPA

cytosol

Traceable author statement. Source: Reactome

neuronal cell body

Inferred from electronic annotation. Source: Ensembl

nuclear envelope

Inferred from electronic annotation. Source: Ensembl

nucleoplasm

Traceable author statement. Source: Reactome

ribonucleoside-diphosphate reductase complex

Inferred from electronic annotation. Source: InterPro

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

RRM2P313503EBI-717006,EBI-2339245

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 792792Ribonucleoside-diphosphate reductase large subunit
PRO_0000187190

Regions

Domain1 – 9292ATP-cone
Region11 – 177Allosteric activator binding By similarity
Region217 – 2182Substrate binding By similarity
Region285 – 2884Allosteric effector binding, determines substrate specificity
Region427 – 4315Substrate binding By similarity
Region603 – 6075Substrate binding By similarity

Sites

Active site4271Proton acceptor By similarity
Active site4291Cysteine radical intermediate By similarity
Active site4311Proton acceptor By similarity
Binding site51Allosteric activator By similarity
Binding site531Allosteric activator By similarity
Binding site881Allosteric activator By similarity
Binding site2021Substrate By similarity
Binding site2471Substrate; via amide nitrogen By similarity
Site2181Important for hydrogen atom transfer By similarity
Site2261Allosteric effector binding, determines substrate specificity
Site2561Allosteric effector binding, determines substrate specificity
Site4441Important for hydrogen atom transfer By similarity
Site7371Important for electron transfer By similarity
Site7381Important for electron transfer By similarity
Site7871Interacts with thioredoxin/glutaredoxin By similarity
Site7901Interacts with thioredoxin/glutaredoxin By similarity

Amino acid modifications

Modified residue171N6-acetyllysine Ref.9
Modified residue3761N6-acetyllysine Ref.9
Disulfide bond218 ↔ 444Redox-active By similarity

Natural variations

Natural variant5901K → Q.
Corresponds to variant rs2228123 [ dbSNP | Ensembl ].
VAR_052052
Natural variant7781V → A.
Corresponds to variant rs2229196 [ dbSNP | Ensembl ].
VAR_052053

Experimental info

Sequence conflict61R → Q in AAD37491. Ref.3

Secondary structure

........................................................................................................................................ 792
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P23921 [UniParc].

Last modified March 1, 1992. Version 1.
Checksum: 4470A76C61E8F86A

FASTA79290,070
        10         20         30         40         50         60 
MHVIKRDGRQ ERVMFDKITS RIQKLCYGLN MDFVDPAQIT MKVIQGLYSG VTTVELDTLA 

        70         80         90        100        110        120 
AETAATLTTK HPDYAILAAR IAVSNLHKET KKVFSDVMED LYNYINPHNG KHSPMVAKST 

       130        140        150        160        170        180 
LDIVLANKDR LNSAIIYDRD FSYNYFGFKT LERSYLLKIN GKVAERPQHM LMRVSVGIHK 

       190        200        210        220        230        240 
EDIDAAIETY NLLSERWFTH ASPTLFNAGT NRPQLSSCFL LSMKDDSIEG IYDTLKQCAL 

       250        260        270        280        290        300 
ISKSAGGIGV AVSCIRATGS YIAGTNGNSN GLVPMLRVYN NTARYVDQGG NKRPGAFAIY 

       310        320        330        340        350        360 
LEPWHLDIFE FLDLKKNTGK EEQRARDLFF ALWIPDLFMK RVETNQDWSL MCPNECPGLD 

       370        380        390        400        410        420 
EVWGEEFEKL YASYEKQGRV RKVVKAQQLW YAIIESQTET GTPYMLYKDS CNRKSNQQNL 

       430        440        450        460        470        480 
GTIKCSNLCT EIVEYTSKDE VAVCNLASLA LNMYVTSEHT YDFKKLAEVT KVVVRNLNKI 

       490        500        510        520        530        540 
IDINYYPVPE ACLSNKRHRP IGIGVQGLAD AFILMRYPFE SAEAQLLNKQ IFETIYYGAL 

       550        560        570        580        590        600 
EASCDLAKEQ GPYETYEGSP VSKGILQYDM WNVTPTDLWD WKVLKEKIAK YGIRNSLLIA 

       610        620        630        640        650        660 
PMPTASTAQI LGNNESIEPY TSNIYTRRVL SGEFQIVNPH LLKDLTERGL WHEEMKNQII 

       670        680        690        700        710        720 
ACNGSIQSIP EIPDDLKQLY KTVWEISQKT VLKMAAERGA FIDQSQSLNI HIAEPNYGKL 

       730        740        750        760        770        780 
TSMHFYGWKQ GLKTGMYYLR TRPAANPIQF TLNKEKLKDK EKVSKEEEEK ERNTAAMVCS 

       790 
LENRDECLMC GS 

« Hide

References

« Hide 'large scale' references
[1]"Human M1 subunit of ribonucleotide reductase: cDNA sequence and expression in stimulated lymphocytes."
Parker N.J., Begley C.G., Fox R.M.
Nucleic Acids Res. 19:3741-3741(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Bone marrow.
[2]"Sequence analysis of the large and small subunits of human ribonucleotide reductase."
Pavloff N., Rivard D., Masson S., Shen S.-H., Mes-Masson A.-M.
DNA Seq. 2:227-234(1992) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Mammary carcinoma.
[3]"A 1.4-Mb high-resolution physical map and contig of chromosome segment 11p15.5 and genes in the LOH11A metastasis suppressor region."
Bepler G., O'Briant K.C., Kim Y.-C., Schreiber G., Pitterle D.M.
Genomics 55:164-175(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Lymph.
[5]"Human R1 subunit of ribonucleotide reductase (RRM1): 5' flanking region of the gene."
Parker N.J., Begley C.G., Fox R.M.
Genomics 19:91-96(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-6.
Tissue: Placenta.
[6]"Human ribonucleotide reductase. Activation and inhibition by analogs of ATP."
Harrington J.A., Spector T.
Biochem. Pharmacol. 42:759-763(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION.
[7]"Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits."
Xue L., Zhou B., Liu X., Qiu W., Jin Z., Yen Y.
Cancer Res. 63:980-986(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RRM2B.
[8]"Characterization of enzymatic properties of human ribonucleotide reductase holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits."
Qiu W., Zhou B., Darwish D., Shao J., Yen Y.
Biochem. Biophys. Res. Commun. 340:428-434(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: CATALYTIC ACTIVITY, SUBUNIT, ENZYME REGULATION.
[9]"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-17 AND LYS-376, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[11]"Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization."
Fairman J.W., Wijerathna S.R., Ahmad M.F., Xu H., Nakano R., Jha S., Prendergast J., Welin R.M., Flodin S., Roos A., Nordlund P., Li Z., Walz T., Dealwis C.G.
Nat. Struct. Mol. Biol. 18:316-322(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 75-742 IN COMPLEX WITH ALLOSTERIC EFFECTOR ATP AND MAGNESIUM IONS.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X59543 mRNA. Translation: CAA42118.1.
X59617 mRNA. Translation: CAA42180.1.
AF107045 Genomic DNA. Translation: AAD37491.1.
BC006498 mRNA. Translation: AAH06498.1.
L10342 Genomic DNA. No translation available.
PIRS16680.
RefSeqNP_001024.1. NM_001033.3.
UniGeneHs.445705.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2WGHX-ray2.30A/B75-742[»]
3HNCX-ray2.41A/B1-792[»]
3HNDX-ray3.21A/B1-792[»]
3HNEX-ray3.11A/B1-792[»]
3HNFX-ray3.16A/B1-792[»]
ProteinModelPortalP23921.
SMRP23921. Positions 14-742.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112154. 19 interactions.
DIPDIP-24233N.
IntActP23921. 4 interactions.
MINTMINT-1406473.
STRING9606.ENSP00000300738.

Chemistry

BindingDBP23921.
ChEMBLCHEMBL2095215.
DrugBankDB00631. Clofarabine.
DB01073. Fludarabine.
DB00441. Gemcitabine.
DB01005. Hydroxyurea.
GuidetoPHARMACOLOGY2630.

PTM databases

PhosphoSiteP23921.

Polymorphism databases

DMDM132608.

Proteomic databases

PaxDbP23921.
PeptideAtlasP23921.
PRIDEP23921.

Protocols and materials databases

DNASU6240.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000300738; ENSP00000300738; ENSG00000167325.
GeneID6240.
KEGGhsa:6240.
UCSCuc001lyw.4. human.

Organism-specific databases

CTD6240.
GeneCardsGC11P004115.
HGNCHGNC:10451. RRM1.
HPACAB022093.
HPA057265.
MIM180410. gene.
neXtProtNX_P23921.
PharmGKBPA298.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0209.
HOGENOMHOG000057035.
HOVERGENHBG003447.
InParanoidP23921.
KOK10807.
OMAKSHIQFY.
OrthoDBEOG7BGHK2.
PhylomeDBP23921.
TreeFamTF300578.

Enzyme and pathway databases

BioCycMetaCyc:HS09541-MONOMER.
ReactomeREACT_111217. Metabolism.
UniPathwayUPA00326.

Gene expression databases

ArrayExpressP23921.
BgeeP23921.
CleanExHS_RRM1.
GenevestigatorP23921.

Family and domain databases

InterProIPR005144. ATP-cone.
IPR013346. NrdE_NrdA.
IPR000788. RNR_lg_C.
IPR013509. RNR_lsu_N.
IPR008926. RNR_R1-su_N.
[Graphical view]
PfamPF03477. ATP-cone. 1 hit.
PF02867. Ribonuc_red_lgC. 1 hit.
PF00317. Ribonuc_red_lgN. 1 hit.
[Graphical view]
PRINTSPR01183. RIBORDTASEM1.
SUPFAMSSF48168. SSF48168. 1 hit.
TIGRFAMsTIGR02506. NrdE_NrdA. 1 hit.
PROSITEPS51161. ATP_CONE. 1 hit.
PS00089. RIBORED_LARGE. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSRRM1. human.
EvolutionaryTraceP23921.
GeneWikiRRM1.
GenomeRNAi6240.
NextBio24233.
PROP23921.
SOURCESearch...

Entry information

Entry nameRIR1_HUMAN
AccessionPrimary (citable) accession number: P23921
Secondary accession number(s): Q9UNN2
Entry history
Integrated into UniProtKB/Swiss-Prot: March 1, 1992
Last sequence update: March 1, 1992
Last modified: April 16, 2014
This is version 148 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM