P23921 (RIR1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	792 AA.
Sequence status	Complete.
Protein existence	Evidence 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 process	DNA replication
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Ligand	ATP-binding Nucleotide-binding
Molecular function	Oxidoreductase
PTM	Acetylation Disulfide bond
Technical term	3D-structure Allosteric enzyme Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	DNA replication Non-traceable author statement. Source: UniProtKB deoxyribonucleotide biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB nucleobase-containing small molecule interconversion Traceable author statement. Source: Reactome protein heterotetramerization Inferred from electronic annotation. Source: Compara
Cellular_component	cytosol Traceable author statement. Source: Reactome nucleoplasm Traceable author statement. Source: Reactome ribonucleoside-diphosphate reductase complex Non-traceable author statement. Source: UniProtKB
Molecular_function	ATP 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
RRM2	P31350	3	EBI-717006,EBI-2339245

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 792

792

Ribonucleoside-diphosphate reductase large subunit

PRO_0000187190

Regions

Domain

1 – 92

92

ATP-cone

Region

11 – 17

7

Allosteric activator binding By similarity

Region

217 – 218

2

Substrate binding By similarity

Region

285 – 288

4

Allosteric effector binding, determines substrate specificity

Region

427 – 431

5

Substrate binding By similarity

Region

603 – 607

5

Substrate binding By similarity

Sites

Active site

427

1

Proton acceptor By similarity

Active site

429

1

Cysteine radical intermediate By similarity

Active site

431

1

Proton acceptor By similarity

Binding site

5

1

Allosteric activator By similarity

Binding site

53

1

Allosteric activator By similarity

Binding site

88

1

Allosteric activator By similarity

Binding site

202

1

Substrate By similarity

Binding site

247

1

Substrate; via amide nitrogen By similarity

Site

218

1

Important for hydrogen atom transfer By similarity

Site

226

1

Allosteric effector binding, determines substrate specificity

Site

256

1

Allosteric effector binding, determines substrate specificity

Site

444

1

Important for hydrogen atom transfer By similarity

Site

737

1

Important for electron transfer By similarity

Site

738

1

Important for electron transfer By similarity

Site

787

1

Interacts with thioredoxin/glutaredoxin By similarity

Site

790

1

Interacts with thioredoxin/glutaredoxin By similarity

Amino acid modifications

Modified residue

17

1

N6-acetyllysine Ref.9

Modified residue

376

1

N6-acetyllysine Ref.9

Disulfide bond

218 ↔ 444

Redox-active By similarity

Natural variations

Natural variant

590

1

K → Q.
Corresponds to variant rs2228123 [ dbSNP | Ensembl ].

VAR_052052

Natural variant

778

1

V → A.
Corresponds to variant rs2229196 [ dbSNP | Ensembl ].

VAR_052053

Experimental info

Sequence conflict

6

1

R → Q in AAD37491. Ref.3

Secondary structure

1

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792

Helix Strand Turn

Details...

Helix

15 – 23

9

Turn

31 – 33

3

Helix

36 – 44

9

Beta strand

48 – 50

3

Helix

53 – 66

14

Helix

67 – 69

3

Helix

78 – 88

11

Helix

94 – 103

10

Turn

107 – 109

3

Helix

118 – 126

9

Helix

128 – 133

6

Helix

137 – 142

6

Helix

145 – 154

10

Beta strand

158 – 163

6

Helix

167 – 179

13

Helix

183 – 195

13

Beta strand

197 – 200

4

Helix

202 – 207

6

Beta strand

210 – 212

3

Beta strand

218 – 222

5

Helix

228 – 243

16

Beta strand

247 – 251

5

Beta strand

258 – 261

4

Helix

263 – 265

3

Beta strand

268 – 270

3

Helix

272 – 285

14

Beta strand

287 – 293

7

Beta strand

297 – 301

5

Helix

308 – 311

4

Turn

312 – 315

4

Beta strand

317 – 319

3

Helix

321 – 323

3

Beta strand

328 – 334

7

Helix

336 – 343

8

Beta strand

347 – 351

5

Turn

353 – 355

3

Helix

359 – 361

3

Helix

365 – 376

12

Beta strand

381 – 385

5

Helix

386 – 400

15

Beta strand

404 – 407

4

Helix

408 – 413

6

Helix

418 – 420

3

Beta strand

428 – 430

3

Beta strand

442 – 444

3

Beta strand

446 – 450

5

Helix

451 – 454

4

Beta strand

459 – 461

3

Helix

463 – 483

21

Helix

489 – 498

10

Beta strand

502 – 506

5

Helix

508 – 514

7

Beta strand

519 – 521

3

Helix

522 – 550

29

Helix

554 – 556

3

Helix

561 – 563

3

Helix

567 – 570

4

Beta strand

577 – 579

3

Helix

581 – 591

11

Helix

607 – 611

5

Beta strand

623 – 629

7

Beta strand

632 – 637

6

Helix

639 – 648

10

Helix

653 – 661

9

Turn

662 – 664

3

Beta strand

670 – 672

3

Helix

674 – 679

6

Turn

683 – 685

3

Helix

688 – 699

12

Helix

717 – 729

13

Beta strand

733 – 737

5

Sequences

	Sequence		Length	Mass (Da)
	P23921 [UniParc]. Last modified March 1, 1992. Version 1. Checksum: 4470A76C61E8F86A	FASTA	792	90,070
	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

References

	« Hide 'large scale' referencesShow '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, MASS SPECTROMETRY.
[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.

Web resources

Wikipedia

Ribonucleotide reductase entry

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.

IPI

IPI00013871.

PIR

S16680.

RefSeq

NP_001024.1. NM_001033.3.

UniGene

Hs.445705.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2WGH	X-ray	2.30	A/B	75-742	[»]
3HNC	X-ray	2.41	A/B	1-792	[»]
3HND	X-ray	3.21	A/B	1-792	[»]
3HNE	X-ray	3.11	A/B	1-792	[»]
3HNF	X-ray	3.16	A/B	1-792	[»]

ProteinModelPortal

P23921.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-24233N.

IntAct

P23921. 4 interactions.

MINT

MINT-1406473.

STRING

9606.ENSP00000300738.

PTM databases

PhosphoSite

P23921.

Polymorphism databases

DMDM

132608.

Proteomic databases

PaxDb

P23921.

PeptideAtlas

P23921.

PRIDE

P23921.

Protocols and materials databases

DNASU

6240.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000300738; ENSP00000300738; ENSG00000167325.

GeneID

6240.

KEGG

hsa:6240.

UCSC

uc001lyw.4. human.

Organism-specific databases

CTD

6240.

GeneCards

GC11P004115.

HGNC

HGNC:10451. RRM1.

HPA

CAB022093.

MIM

180410. gene.

neXtProt

NX_P23921.

PharmGKB

PA298.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0209.

HOGENOM

HOG000057035.

HOVERGEN

HBG003447.

InParanoid

P23921.

KO

K10807.

OMA

PQARNSN.

OrthoDB

EOG4ZW59G.

PhylomeDB

P23921.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

UniPathway

UPA00326.

Gene expression databases

ArrayExpress

P23921.

Bgee

P23921.

CleanEx

HS_RRM1.

Genevestigator

P23921.

GermOnline

ENSG00000167325. Homo sapiens.

Family and domain databases

InterPro

IPR005144. ATP-cone.
IPR013346. NrdE_NrdA.
IPR000788. RNR_lg_C.
IPR013509. RNR_lsu_N.
IPR008926. RNR_R1-su_N.
[Graphical view]

Pfam

PF03477. ATP-cone. 1 hit.
PF02867. Ribonuc_red_lgC. 1 hit.
PF00317. Ribonuc_red_lgN. 1 hit.
[Graphical view]

PRINTS

PR01183. RIBORDTASEM1.

SUPFAM

SSF48168. Ribonucleo_red_N. 1 hit.

TIGRFAMs

TIGR02506. NrdE_NrdA. 1 hit.

PROSITE

PS51161. ATP_CONE. 1 hit.
PS00089. RIBORED_LARGE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P23921.

ChEMBL

CHEMBL1830.

ChiTaRS

RRM1. human.

DrugBank

DB00631. Clofarabine.
DB01073. Fludarabine.
DB00441. Gemcitabine.
DB01005. Hydroxyurea.

EvolutionaryTrace

P23921.

GenomeRNAi

6240.

NextBio

24233.

SOURCE

Search...

Entry information

Entry name

RIR1_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 138 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.