EzCatDB: M00047

DB codeM00047
CATH domainDomain 1-.-.-.-
Domain 21.10.10.41
Domain 32.170.11.10
Domain 43.90.15.10Catalytic domain
Domain 51.10.132.10Catalytic domain
E.C.5.99.1.2
CSA1k4t

CATH domainRelated DB codes (homologues)
1.10.10.41M00182
1.10.132.10M00182
2.170.11.10M00182
3.90.15.10T00228,M00182

Enzyme Name
Swiss-protKEGG

P11387
Protein nameDNA topoisomerase 1DNA topoisomerase
type I DNA topoisomerase
untwisting enzyme
relaxing enzyme
nicking-closing enzyme
swivelase
omega-protein
deoxyribonucleate topoisomerase
topoisomerase
type I DNA topoisomerase
SynonymsEC 5.99.1.2
DNA topoisomerase I


Swiss-prot:Accession NumberP11387
Entry nameTOP1_HUMAN
ActivityATP-independent breakage of single-stranded DNA, followed by passage and rejoining.
SubunitMonomer.
Subcellular locationNucleus, nucleolus. Nucleus, nucleoplasm. Note=Diffuse nuclear localization with some enrichment in nucleoli. On CPT treatment, cleared from nucleoli into nucleoplasm. Sumolyated forms found in both nucleoplasm and nucleoli.
Cofactor


SubstratesProductsintermediates
KEGG-idC00271C00271
CompoundSingle-stranded DNASingle-stranded DNA
Typenucleic acidsnucleic acids
1a31A01UnboundUnboundUnbound
1a35A01UnboundUnboundUnbound
1a36A01UnboundUnboundUnbound
1ej9A01UnboundUnboundUnbound
1k4sA01UnboundUnboundUnbound
1k4tA01UnboundUnboundUnbound
1lpqA01UnboundUnboundUnbound
1nh3A01UnboundUnboundUnbound
1r49A01UnboundUnboundUnbound
1rr8C01UnboundUnboundUnbound
1rrjA01UnboundUnboundUnbound
1sc7A01UnboundUnboundUnbound
1seuA01UnboundUnboundUnbound
1t8iA01UnboundUnboundUnbound
1tl8A01UnboundUnboundUnbound
1a31A02UnboundUnboundUnbound
1a35A02UnboundUnboundUnbound
1a36A02UnboundUnboundUnbound
1ej9A02UnboundUnboundUnbound
1k4sA02UnboundUnboundUnbound
1k4tA02UnboundUnboundUnbound
1lpqA02UnboundUnboundUnbound
1nh3A02UnboundUnboundUnbound
1r49A02UnboundUnboundUnbound
1rr8C02UnboundUnboundUnbound
1rrjA02UnboundUnboundUnbound
1sc7A02UnboundUnboundUnbound
1seuA02UnboundUnboundUnbound
1t8iA02UnboundUnboundUnbound
1tl8A02UnboundUnboundUnbound
1a31A03Analogue:A-A-A-A-A-T-5IU-5IU-5IU-5IU-C-A-A-A-G-T-C-T-T-T-T-T(chain D)UnboundUnbound
1a35A03Analogue:A-A-A-A-A-T-BRU-BRU-BRU-BRU-C-BRU-A-A-G-T-C-T-T-T-BRU-T(chain D)UnboundUnbound
1a36A03Bound:A-A-A-A-A-T-T-T-T-T-C-T-A-A-G-T-C-T-T-T-T-T(chain C)UnboundUnbound
1ej9A03Bound:A-A-A-A-A-T-T-T-T-T-C-T-G-A-G-T-C-T-T-T-T-T(chain D)UnboundUnbound
1k4sA03Analogue:A-A-A-A-A-T-5IU-5IU-5IU-5IU-C-A-A-A-G-5IU-C-5IU-5IU-5IU-5IU-T(chain D)UnboundUnbound
1k4tA03Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T(chain D)UnboundUnbound
1lpqA03Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T(chain C)UnboundUnbound
1nh3A03Analogue:A-A-A-A-A-T-U-U-U-U-C-CAR-A-A-G-U-C-U-U-U-U-T(chain D)UnboundUnbound
1r49A03Bound:A-A-A-A-A-T-T-T-T-T-C-T-A-A-G-T-C-T-T-T-T-T(chain C)UnboundUnbound
1rr8C03Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T(chain B)UnboundUnbound
1rrjA03Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T(chain C)UnboundUnbound
1sc7A03Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T(chain D)UnboundUnbound
1seuA03Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T(chain D)UnboundUnbound
1t8iA03Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T(chain D)UnboundUnbound
1tl8A03Bound:A-A-A-A-A-T-T-T-T-T-C-G-A-A-G-T-C-T-T-T-T-T(chain D)UnboundUnbound
1a31A04Analogue:T-G-A-A-A-A-A-5IU-5IU-5IU-5IU-T(chain C)UnboundIntermediate-analogue:A-A-A-A-A-G-A-C-5IU-5IU 10-PTR 723(chain C)
1a35A04Analogue:A-A-A-A-A-G-A-C-T-T-A-G-A-A-A-A-A-BRU-BRU-T-T-T(chain C)UnboundUnbound
1a36A04Bound:A-A-A-A-A-G-A-C-T-T-A-G-A-A-A-A-A-T-T-T-T-T(chain B)UnboundUnbound
1ej9A04Bound:A-A-A-A-A-G-A-C-T-C-A-G-A-A-A-A-A-T-T-T-T-T(chain C)UnboundUnbound
1k4sA04Analogue:SPT-G-A-A-A-A-A-5IU-5IU-5IU-5IU-T(chain C)UnboundIntermediate-analogue:A-A-A-A-A-G-A-C-5IU-5IU 10-PTR 723(chain B)
1k4tA04Analogue:TGP-G-A-A-A-A-A-T-T-T-T-T(chain C)UnboundIntermediate-bound:A-A-A-A-A-G-A-C-T-T_10-PTR 723(chain B)
1lpqA04Bound:A-A-A-A-A-G-A-C-T-T-8OG-G-A-A-A-A-A-T-T-T-T-T(chain B)UnboundUnbound
1nh3A04Analogue:GNG-G-A-A-A-A-A-U-U-U-U-T(chain C)UnboundIntermediate-analogue:A-A-A-A-A-G-A-C-U-UBB 10-PTR 723(chain B)
1r49A04Bound:A-A-A-A-A-G-A-C-T-T-A-G-A-A-A-A-A-T-T-T-T-T(chain B)UnboundUnbound
1rr8C04Bound:G-G-A-A-A-A-A-T-T-T-T-T(chain A)UnboundIntermediate-analogue:A-A-A-A-A-G-A-C-T-T_10-PTR 723(chain A)
1rrjA04Bound:G-G-A-A-A-A-A-T-T-T-T-T(chain B)UnboundIntermediate-analogue:A-A-A-A-A-G-A-C-T-T_10-PTR 723(chain B)
1sc7A04Analogue:TGP-G-A-A-A-A-A-T-T-T-T-T(chain C)UnboundIntermediate-bound:A-A-A-A-A-G-A-C-T-T_10-PTR 723(chain B)
1seuA04Analogue:TGP-G-A-A-A-A-A-T-T-T-T-T(chain C)UnboundIntermediate-bound:A-A-A-A-A-G-A-C-T-T_10-PTR 723(chain B)
1t8iA04Analogue:TGP-G-A-A-A-A-A-T-T-T-T-T(chain C)UnboundIntermediate-bound:A-A-A-A-A-G-A-C-T-T_10-PTR 723(chain B)
1tl8A04Analogue:TPC-G-A-A-A-A-A-T-T-T-T-T(chain C)UnboundIntermediate-bound:A-A-A-A-A-G-A-C-T-T_10-PTR 723(chain B)

Active-site residues
resource
Literature
pdbCatalytic residuesModified residuescomment
1a31A01


1a35A01


1a36A01


1ej9A01


1k4sA01


1k4tA01


1lpqA01


1nh3A01


1r49A01


1rr8C01


1rrjA01


1sc7A01


1seuA01


1t8iA01


1tl8A01


1a31A02


1a35A02


1a36A02


1ej9A02


1k4sA02


1k4tA02


1lpqA02


1nh3A02


1r49A02


1rr8C02


1rrjA02


1sc7A02


1seuA02


1t8iA02


1tl8A02


1a31A03ARG 488;LYS 532


1a35A03ARG 488;LYS 532


1a36A03ARG 488;LYS 532


1ej9A03ARG 488;LYS 532


1k4sA03ARG 488;LYS 532


1k4tA03ARG 488;LYS 532


1lpqA03ARG 488;LYS 532


1nh3A03ARG 488;LYS 532


1r49A03ARG 488;       

mutant K532R
1rr8C03ARG 488;LYS 532


1rrjA03ARG 488;LYS 532


1sc7A03ARG 488;LYS 532


1seuA03ARG 488;LYS 532


1t8iA03ARG 488;LYS 532


1tl8A03ARG 488;LYS 532


1a31A04ARG 590;       ;       
PTR 723(Phosphorylated Tyr)
invisible 627-640, 713-719
1a35A04ARG 590;HIS 632;       
                           
mutant Y723F
1a36A04ARG 590;HIS 632;       
                           
mutant Y723F
1ej9A04ARG 590;HIS 632;       
                           
mutant Y723F
1k4sA04ARG 590;HIS 632;       
PTR 723(Phosphorylated Tyr)

1k4tA04ARG 590;HIS 632;       
PTR 723(Phosphorylated Tyr)

1lpqA04ARG 590;HIS 632;       
                           
mutant Y723F
1nh3A04ARG 590;       ;       
PTR 723(Phosphorylated Tyr)
invisible 627-640, 713-718
1r49A04ARG 590;HIS 632;       
                           
mutant Y723F
1rr8C04ARG 590;HIS 632;       
PTR 723(Phosphorylated Tyr)

1rrjA04ARG 590;HIS 632;       
PTR 723(Phosphorylated Tyr)

1sc7A04ARG 590;HIS 632;       
PTR 723(Phosphorylated Tyr)

1seuA04ARG 590;HIS 632;       
PTR 723(Phosphorylated Tyr)

1t8iA04ARG 590;HIS 632;       
PTR 723(Phosphorylated Tyr)

1tl8A04ARG 590;HIS 632;       
PTR 723(Phosphorylated Tyr)


References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[3]p.76-77
[4]Fig.1
[5]p.2-4
[9]Fig.1
[10]p.1511
[11]Fig.3, Fig.4, p.1538-15402
[12]p.687-694
[15]p.6836-6840
[19]

[23]p.12104-12105
[25]p.12464-12465
[27]p.2991-2992

references
[1]
PubMed ID2852543
JournalCell Biol Int Rep
Year1988
Volume12
Pages927-30
AuthorsHolmstrom M
TitleHomology at a possible catalytic site in DNA topoisomerase I.
[2]
PubMed ID8382801
JournalNucleic Acids Res
Year1993
Volume21
Pages593-600
AuthorsGromova II, Kjeldsen E, Svejstrup JQ, Alsner J, Christiansen K, Westergaard O
TitleCharacterization of an altered DNA catalysis of a camptothecin-resistant eukaryotic topoisomerase I.
[3]
PubMed ID7826865
JournalAdv Pharmacol
Year1994
Volume29A
Pages71-82
AuthorsChampoux JJ
TitleMechanism of catalysis by eukaryotic DNA topoisomerase I.
[4]
PubMed ID8157668
JournalJ Biol Chem
Year1994
Volume269
Pages11367-73
AuthorsChristiansen K, Knudsen BR, Westergaard O
TitleThe covalent eukaryotic topoisomerase I-DNA intermediate catalyzes pH-dependent hydrolysis and alcoholysis.
[5]
PubMed ID7772596
JournalBiochim Biophys Acta
Year1995
Volume1262
Pages1-14
AuthorsGupta M, Fujimori A, Pommier Y
TitleEukaryotic DNA topoisomerases I.
[6]
PubMed ID7867711
JournalExp Cell Res
Year1995
Volume217
Pages125-31
AuthorsD'Arpa P, Liu LF
TitleCell cycle-specific and transcription-related phosphorylation of mammalian topoisomerase I.
[7]
PubMed ID9180386
JournalAnticancer Drugs
Year1997
Volume8
Pages336-44
AuthorsPond CD, Holden JA, Schnabel PC, Barrows LR
TitleSurface plasmon resonance analysis of topoisomerase I-DNA binding: effect of Mg2+ and DNA sequence.
[8]
PubMed ID9174116
JournalBiochem Pharmacol
Year1997
Volume53
Pages1019-27
AuthorsLi XG, Haluska P Jr, Hsiang YH, Bharti AK, Kufe DW, Liu LF, Rubin EH
TitleInvolvement of amino acids 361 to 364 of human topoisomerase I in camptothecin resistance and enzyme catalysis.
[9]
PubMed ID9428510
JournalCell
Year1997
Volume91
Pages873-4
AuthorsBurgin AB Jr
TitleCan DNA topoisomerases be ribonucleases?
[10]
CommentsX-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 215-765.
Medline ID98155246
PubMed ID9488644
JournalScience
Year1998
Volume279
Pages1504-13
AuthorsRedinbo MR, Stewart L, Kuhn P, Champoux JJ, Hol WG
TitleCrystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA.
Related PDB1a31,1a35
Related Swiss-protP11387
[11]
CommentsX-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 215-765.
Medline ID98155254
PubMed ID9488652
JournalScience
Year1998
Volume279
Pages1534-41
AuthorsStewart L, Redinbo MR, Qiu X, Hol WG, Champoux JJ
TitleA model for the mechanism of human topoisomerase I.
Related PDB1a36
Related Swiss-protP11387
[12]
PubMed ID10497031
JournalJ Mol Biol
Year1999
Volume292
Pages685-96
AuthorsRedinbo MR, Stewart L, Champoux JJ, Hol WG
TitleStructural flexibility in human topoisomerase I revealed in multiple non-isomorphous crystal structures.
[13]
PubMed ID10570037
JournalMol Pharmacol
Year1999
Volume56
Pages1105-15
AuthorsFiorani P, Amatruda JF, Silvestri A, Butler RH, Bjornsti MA, Benedetti P
TitleDomain interactions affecting human DNA topoisomerase I catalysis and camptothecin sensitivity.
[14]
PubMed ID10380229
JournalPac Symp Biocomput
Year1999
Volume
Pages578-89
AuthorsShaiu WL, Hu T, Hsieh TS
TitleThe hydrophilic, protease-sensitive terminal domains of eucaryotic DNA topoisomerases have essential intracellular functions.
[15]
CommentsX-ray crystallography
PubMed ID10841763
JournalBiochemistry
Year2000
Volume39
Pages6832-40
AuthorsRedinbo MR, Champoux JJ, Hol WG
TitleNovel insights into catalytic mechanism from a crystal structure of human topoisomerase I in complex with DNA.
Related PDB1ej9
[16]
PubMed ID11034544
JournalAdv Cancer Res
Year2001
Volume80
Pages189-216
AuthorsPourquier P, Pommier Y
TitleTopoisomerase I-mediated DNA damage.
[17]
PubMed ID11423431
JournalBiophys J
Year2001
Volume81
Pages490-500
AuthorsChillemi G, Castrignano T, Desideri A
TitleStructure and hydration of the DNA-human topoisomerase I covalent complex.
[18]
PubMed ID11280753
JournalCancer Res
Year2001
Volume61
Pages1964-9
AuthorsUrasaki Y, Laco GS, Pourquier P, Takebayashi Y, Kohlhagen G, Gioffre C, Zhang H, Chatterjee D, Pantazis P, Pommier Y
TitleCharacterization of a novel topoisomerase I mutation from a camptothecin-resistant human prostate cancer cell line.
[19]
PubMed ID11024057
JournalJ Biol Chem
Year2001
Volume276
Pages677-85
AuthorsYang Z, Champoux JJ
TitleThe role of histidine 632 in catalysis by human topoisomerase I.
[20]
PubMed ID11283003
JournalJ Biol Chem
Year2001
Volume276
Pages20220-7
AuthorsLisby M, Olesen JR, Skouboe C, Krogh BO, Straub T, Boege F, Velmurugan S, Martensen PM, Andersen AH, Jayaram M, Westergaard O, Knudsen BR
TitleResidues within the N-terminal domain of human topoisomerase I play a direct role in relaxation.
[21]
PubMed ID11809893
JournalNucleic Acids Res
Year2002
Volume30
Pages794-802
AuthorsDas A, Mandal C, Dasgupta A, Sengupta T, Majumder HK
TitleAn insight into the active site of a type I DNA topoisomerase from the kinetoplastid protozoan Leishmania donovani.
[22]
PubMed ID12439742
JournalOncogene
Year2002
Volume21
Pages7913-22
AuthorsHorie K, Tomida A, Sugimoto Y, Yasugi T, Yoshikawa H, Taketani Y, Tsuruo T
TitleSUMO-1 conjugation to intact DNA topoisomerase I amplifies cleavable complex formation induced by camptothecin.
[23]
PubMed ID12209008
JournalProc Natl Acad Sci U S A
Year2002
Volume99
Pages12102-7
AuthorsLesher DT, Pommier Y, Stewart L, Redinbo MR
Title8-Oxoguanine rearranges the active site of human topoisomerase I.
Related PDB1lpq
[24]
PubMed ID12426403
JournalProc Natl Acad Sci U S A
Year2002
Volume99
Pages15387-92
AuthorsStaker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L
TitleThe mechanism of topoisomerase I poisoning by a camptothecin analog.
Related PDB1k4s,1k4t
[25]
PubMed ID12533542
JournalJ Biol Chem
Year2003
Volume278
Pages12461-6
AuthorsChrencik JE, Burgin AB, Pommier Y, Stewart L, Redinbo MR
TitleStructural impact of the leukemia drug 1-beta-D-arabinofuranosylcytosine (Ara-C) on the covalent human topoisomerase I-DNA complex.
Related PDB1nh3
[26]
PubMed ID12595561
JournalNucleic Acids Res
Year2003
Volume31
Pages1525-35
AuthorsChillemi G, Fiorani P, Benedetti P, Desideri A
TitleProtein concerted motions in the DNA-human topoisomerase I complex.
[27]
PubMed ID14594810
JournalJ Biol Chem
Year2004
Volume279
Pages2984-92
AuthorsInterthal H, Quigley PM, Hol WG, Champoux JJ
TitleThe role of lysine 532 in the catalytic mechanism of human topoisomerase I.
Related PDB1r49
[28]
PubMed ID15165849
JournalJ Mol Biol
Year2004
Volume339
Pages773-84
AuthorsChrencik JE, Staker BL, Burgin AB, Pourquier P, Pommier Y, Stewart L, Redinbo MR
TitleMechanisms of camptothecin resistance by human topoisomerase I mutations.
Related PDB1rr8,1rrj
[29]
PubMed ID15801827
JournalJ Med Chem
Year2005
Volume48
Pages2336-45
AuthorsStaker BL, Feese MD, Cushman M, Pommier Y, Zembower D, Stewart L, Burgin AB
TitleStructures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex.
Related PDB1sc7,1seu,1t8i
[30]
PubMed ID16033260
JournalJ Med Chem
Year2005
Volume48
Pages4803-14
AuthorsIoanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M
TitleSynthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a flipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by X-ray crystallographic analysis.
Related PDB1tl8

comments
This enzyme must be composed of at least five domains. Although the structure of the N-terminal domain has not been solved yet, its catalytic domain has been elucidated.

createdupdated
2004-04-272009-02-26
Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2010)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)

© Computational Biology Research Center, AIST, 2004 All Rights Reserved.