DB code: M00047

CATH domain -.-.-.- :
1.10.10.41 : Arc Repressor Mutant, subunit A
2.170.11.10 : DNA Topoisomerase I; domain 2
3.90.15.10 : Topoisomerase I; Chain A, domain 3 Catalytic domain
1.10.132.10 : Topoisomerase I; Chain A, domain 4 Catalytic domain
E.C. 5.99.1.2
CSA 1k4t
M-CSA 1k4t
MACiE

CATH domain Related DB codes (homologues)
1.10.10.41 : Arc Repressor Mutant, subunit A M00182
1.10.132.10 : Topoisomerase I; Chain A, domain 4 M00182
2.170.11.10 : DNA Topoisomerase I; domain 2 M00182
3.90.15.10 : Topoisomerase I; Chain A, domain 3 T00228 M00182

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P11387 DNA topoisomerase 1
EC 5.99.1.2
DNA topoisomerase I
NP_003277.1 (Protein)
NM_003286.2 (DNA/RNA sequence)
PF14370 (Topo_C_assoc)
PF01028 (Topoisom_I)
PF02919 (Topoisom_I_N)
[Graphical View]

KEGG enzyme name
DNA topoisomerase
type I DNA topoisomerase
untwisting enzyme
relaxing enzyme
nicking-closing enzyme
swivelase
omega-protein
deoxyribonucleate topoisomerase
topoisomerase
type I DNA topoisomerase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P11387 TOP1_HUMAN ATP-independent breakage of single-stranded DNA, followed by passage and rejoining. Monomer. Nucleus, 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.

KEGG Pathways
Map code Pathways E.C.

Compound table
Substrates Products Intermediates
KEGG-id C00271 C00271
E.C.
Compound Single-stranded DNA Single-stranded DNA
Type nucleic acids nucleic acids
ChEBI
PubChem
1a31A01 Unbound Unbound Unbound
1a35A01 Unbound Unbound Unbound
1a36A01 Unbound Unbound Unbound
1ej9A01 Unbound Unbound Unbound
1k4sA01 Unbound Unbound Unbound
1k4tA01 Unbound Unbound Unbound
1lpqA01 Unbound Unbound Unbound
1nh3A01 Unbound Unbound Unbound
1r49A01 Unbound Unbound Unbound
1rr8C01 Unbound Unbound Unbound
1rrjA01 Unbound Unbound Unbound
1sc7A01 Unbound Unbound Unbound
1seuA01 Unbound Unbound Unbound
1t8iA01 Unbound Unbound Unbound
1tl8A01 Unbound Unbound Unbound
1a31A02 Unbound Unbound Unbound
1a35A02 Unbound Unbound Unbound
1a36A02 Unbound Unbound Unbound
1ej9A02 Unbound Unbound Unbound
1k4sA02 Unbound Unbound Unbound
1k4tA02 Unbound Unbound Unbound
1lpqA02 Unbound Unbound Unbound
1nh3A02 Unbound Unbound Unbound
1r49A02 Unbound Unbound Unbound
1rr8C02 Unbound Unbound Unbound
1rrjA02 Unbound Unbound Unbound
1sc7A02 Unbound Unbound Unbound
1seuA02 Unbound Unbound Unbound
1t8iA02 Unbound Unbound Unbound
1tl8A02 Unbound Unbound Unbound
1a31A03 Analogue:A-A-A-A-A-T-5IU-5IU-5IU-5IU-C-A-A-A-G-T-C-T-T-T-T-T (chain D) Unbound Unbound
1a35A03 Analogue:A-A-A-A-A-T-BRU-BRU-BRU-BRU-C-BRU-A-A-G-T-C-T-T-T-BRU-T (chain D) Unbound Unbound
1a36A03 Bound:A-A-A-A-A-T-T-T-T-T-C-T-A-A-G-T-C-T-T-T-T-T (chain C) Unbound Unbound
1ej9A03 Bound:A-A-A-A-A-T-T-T-T-T-C-T-G-A-G-T-C-T-T-T-T-T (chain D) Unbound Unbound
1k4sA03 Analogue:A-A-A-A-A-T-5IU-5IU-5IU-5IU-C-A-A-A-G-5IU-C-5IU-5IU-5IU-5IU-T (chain D) Unbound Unbound
1k4tA03 Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T (chain D) Unbound Unbound
1lpqA03 Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T (chain C) Unbound Unbound
1nh3A03 Analogue:A-A-A-A-A-T-U-U-U-U-C-CAR-A-A-G-U-C-U-U-U-U-T (chain D) Unbound Unbound
1r49A03 Bound:A-A-A-A-A-T-T-T-T-T-C-T-A-A-G-T-C-T-T-T-T-T (chain C) Unbound Unbound
1rr8C03 Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T (chain B) Unbound Unbound
1rrjA03 Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T (chain C) Unbound Unbound
1sc7A03 Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T (chain D) Unbound Unbound
1seuA03 Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T (chain D) Unbound Unbound
1t8iA03 Bound:A-A-A-A-A-T-T-T-T-T-C-C-A-A-G-T-C-T-T-T-T-T (chain D) Unbound Unbound
1tl8A03 Bound:A-A-A-A-A-T-T-T-T-T-C-G-A-A-G-T-C-T-T-T-T-T (chain D) Unbound Unbound
1a31A04 Analogue:T-G-A-A-A-A-A-5IU-5IU-5IU-5IU-T (chain C) Unbound Intermediate-analogue:A-A-A-A-A-G-A-C-5IU-5IU_10-PTR_723 (chain C)
1a35A04 Analogue:A-A-A-A-A-G-A-C-T-T-A-G-A-A-A-A-A-BRU-BRU-T-T-T (chain C) Unbound Unbound
1a36A04 Bound:A-A-A-A-A-G-A-C-T-T-A-G-A-A-A-A-A-T-T-T-T-T (chain B) Unbound Unbound
1ej9A04 Bound:A-A-A-A-A-G-A-C-T-C-A-G-A-A-A-A-A-T-T-T-T-T (chain C) Unbound Unbound
1k4sA04 Analogue:SPT-G-A-A-A-A-A-5IU-5IU-5IU-5IU-T (chain C) Unbound Intermediate-analogue:A-A-A-A-A-G-A-C-5IU-5IU_10-PTR_723 (chain B)
1k4tA04 Analogue:TGP-G-A-A-A-A-A-T-T-T-T-T (chain C) Unbound Intermediate-bound:A-A-A-A-A-G-A-C-T-T_10-PTR_723 (chain B)
1lpqA04 Bound:A-A-A-A-A-G-A-C-T-T-8OG-G-A-A-A-A-A-T-T-T-T-T (chain B) Unbound Unbound
1nh3A04 Analogue:GNG-G-A-A-A-A-A-U-U-U-U-T (chain C) Unbound Intermediate-analogue:A-A-A-A-A-G-A-C-U-UBB_10-PTR_723 (chain B)
1r49A04 Bound:A-A-A-A-A-G-A-C-T-T-A-G-A-A-A-A-A-T-T-T-T-T (chain B) Unbound Unbound
1rr8C04 Bound:G-G-A-A-A-A-A-T-T-T-T-T (chain A) Unbound Intermediate-analogue:A-A-A-A-A-G-A-C-T-T_10-PTR_723 (chain A)
1rrjA04 Bound:G-G-A-A-A-A-A-T-T-T-T-T (chain B) Unbound Intermediate-analogue:A-A-A-A-A-G-A-C-T-T_10-PTR_723 (chain B)
1sc7A04 Analogue:TGP-G-A-A-A-A-A-T-T-T-T-T (chain C) Unbound Intermediate-bound:A-A-A-A-A-G-A-C-T-T_10-PTR_723 (chain B)
1seuA04 Analogue:TGP-G-A-A-A-A-A-T-T-T-T-T (chain C) Unbound Intermediate-bound:A-A-A-A-A-G-A-C-T-T_10-PTR_723 (chain B)
1t8iA04 Analogue:TGP-G-A-A-A-A-A-T-T-T-T-T (chain C) Unbound Intermediate-bound:A-A-A-A-A-G-A-C-T-T_10-PTR_723 (chain B)
1tl8A04 Analogue:TPC-G-A-A-A-A-A-T-T-T-T-T (chain C) Unbound Intermediate-bound:A-A-A-A-A-G-A-C-T-T_10-PTR_723 (chain B)

Reference for Active-site residues
resource references E.C.
Literature

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
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
1a31A03 ARG 488;LYS 532
1a35A03 ARG 488;LYS 532
1a36A03 ARG 488;LYS 532
1ej9A03 ARG 488;LYS 532
1k4sA03 ARG 488;LYS 532
1k4tA03 ARG 488;LYS 532
1lpqA03 ARG 488;LYS 532
1nh3A03 ARG 488;LYS 532
1r49A03 ARG 488; mutant K532R
1rr8C03 ARG 488;LYS 532
1rrjA03 ARG 488;LYS 532
1sc7A03 ARG 488;LYS 532
1seuA03 ARG 488;LYS 532
1t8iA03 ARG 488;LYS 532
1tl8A03 ARG 488;LYS 532
1a31A04 ARG 590; ; PTR 723(Phosphorylated Tyr) invisible 627-640, 713-719
1a35A04 ARG 590;HIS 632; mutant Y723F
1a36A04 ARG 590;HIS 632; mutant Y723F
1ej9A04 ARG 590;HIS 632; mutant Y723F
1k4sA04 ARG 590;HIS 632; PTR 723(Phosphorylated Tyr)
1k4tA04 ARG 590;HIS 632; PTR 723(Phosphorylated Tyr)
1lpqA04 ARG 590;HIS 632; mutant Y723F
1nh3A04 ARG 590; ; PTR 723(Phosphorylated Tyr) invisible 627-640, 713-718
1r49A04 ARG 590;HIS 632; mutant Y723F
1rr8C04 ARG 590;HIS 632; PTR 723(Phosphorylated Tyr)
1rrjA04 ARG 590;HIS 632; PTR 723(Phosphorylated Tyr)
1sc7A04 ARG 590;HIS 632; PTR 723(Phosphorylated Tyr)
1seuA04 ARG 590;HIS 632; PTR 723(Phosphorylated Tyr)
1t8iA04 ARG 590;HIS 632; PTR 723(Phosphorylated Tyr)
1tl8A04 ARG 590;HIS 632; PTR 723(Phosphorylated Tyr)

References for Catalytic Mechanism
References Sections No. 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.1538-1540 2
[12]
p.687-694
[15]
p.6836-6840
[19]
[23]
p.12104-12105
[25]
p.12464-12465
[27]
p.2991-2992

References
[1]
Resource
Comments
Medline ID
PubMed ID 2852543
Journal Cell Biol Int Rep
Year 1988
Volume 12
Pages 927-30
Authors Holmstrom M
Title Homology at a possible catalytic site in DNA topoisomerase I.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 8382801
Journal Nucleic Acids Res
Year 1993
Volume 21
Pages 593-600
Authors Gromova II, Kjeldsen E, Svejstrup JQ, Alsner J, Christiansen K, Westergaard O
Title Characterization of an altered DNA catalysis of a camptothecin-resistant eukaryotic topoisomerase I.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 7826865
Journal Adv Pharmacol
Year 1994
Volume 29A
Pages 71-82
Authors Champoux JJ
Title Mechanism of catalysis by eukaryotic DNA topoisomerase I.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 8157668
Journal J Biol Chem
Year 1994
Volume 269
Pages 11367-73
Authors Christiansen K, Knudsen BR, Westergaard O
Title The covalent eukaryotic topoisomerase I-DNA intermediate catalyzes pH-dependent hydrolysis and alcoholysis.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 7772596
Journal Biochim Biophys Acta
Year 1995
Volume 1262
Pages 1-14
Authors Gupta M, Fujimori A, Pommier Y
Title Eukaryotic DNA topoisomerases I.
Related PDB
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 7867711
Journal Exp Cell Res
Year 1995
Volume 217
Pages 125-31
Authors D'Arpa P, Liu LF
Title Cell cycle-specific and transcription-related phosphorylation of mammalian topoisomerase I.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 9180386
Journal Anticancer Drugs
Year 1997
Volume 8
Pages 336-44
Authors Pond CD, Holden JA, Schnabel PC, Barrows LR
Title Surface plasmon resonance analysis of topoisomerase I-DNA binding: effect of Mg2+ and DNA sequence.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 9174116
Journal Biochem Pharmacol
Year 1997
Volume 53
Pages 1019-27
Authors Li XG, Haluska P Jr, Hsiang YH, Bharti AK, Kufe DW, Liu LF, Rubin EH
Title Involvement of amino acids 361 to 364 of human topoisomerase I in camptothecin resistance and enzyme catalysis.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 9428510
Journal Cell
Year 1997
Volume 91
Pages 873-4
Authors Burgin AB Jr
Title Can DNA topoisomerases be ribonucleases?
Related PDB
Related UniProtKB
[10]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 215-765.
Medline ID 98155246
PubMed ID 9488644
Journal Science
Year 1998
Volume 279
Pages 1504-13
Authors Redinbo MR, Stewart L, Kuhn P, Champoux JJ, Hol WG
Title Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA.
Related PDB 1a31 1a35
Related UniProtKB P11387
[11]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 215-765.
Medline ID 98155254
PubMed ID 9488652
Journal Science
Year 1998
Volume 279
Pages 1534-41
Authors Stewart L, Redinbo MR, Qiu X, Hol WG, Champoux JJ
Title A model for the mechanism of human topoisomerase I.
Related PDB 1a36
Related UniProtKB P11387
[12]
Resource
Comments
Medline ID
PubMed ID 10497031
Journal J Mol Biol
Year 1999
Volume 292
Pages 685-96
Authors Redinbo MR, Stewart L, Champoux JJ, Hol WG
Title Structural flexibility in human topoisomerase I revealed in multiple non-isomorphous crystal structures.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 10570037
Journal Mol Pharmacol
Year 1999
Volume 56
Pages 1105-15
Authors Fiorani P, Amatruda JF, Silvestri A, Butler RH, Bjornsti MA, Benedetti P
Title Domain interactions affecting human DNA topoisomerase I catalysis and camptothecin sensitivity.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 10380229
Journal Pac Symp Biocomput
Year 1999
Volume
Pages 578-89
Authors Shaiu WL, Hu T, Hsieh TS
Title The hydrophilic, protease-sensitive terminal domains of eucaryotic DNA topoisomerases have essential intracellular functions.
Related PDB
Related UniProtKB
[15]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 10841763
Journal Biochemistry
Year 2000
Volume 39
Pages 6832-40
Authors Redinbo MR, Champoux JJ, Hol WG
Title Novel insights into catalytic mechanism from a crystal structure of human topoisomerase I in complex with DNA.
Related PDB 1ej9
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 11034544
Journal Adv Cancer Res
Year 2001
Volume 80
Pages 189-216
Authors Pourquier P, Pommier Y
Title Topoisomerase I-mediated DNA damage.
Related PDB
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID 11423431
Journal Biophys J
Year 2001
Volume 81
Pages 490-500
Authors Chillemi G, Castrignano T, Desideri A
Title Structure and hydration of the DNA-human topoisomerase I covalent complex.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 11280753
Journal Cancer Res
Year 2001
Volume 61
Pages 1964-9
Authors Urasaki Y, Laco GS, Pourquier P, Takebayashi Y, Kohlhagen G, Gioffre C, Zhang H, Chatterjee D, Pantazis P, Pommier Y
Title Characterization of a novel topoisomerase I mutation from a camptothecin-resistant human prostate cancer cell line.
Related PDB
Related UniProtKB
[19]
Resource
Comments
Medline ID
PubMed ID 11024057
Journal J Biol Chem
Year 2001
Volume 276
Pages 677-85
Authors Yang Z, Champoux JJ
Title The role of histidine 632 in catalysis by human topoisomerase I.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID 11283003
Journal J Biol Chem
Year 2001
Volume 276
Pages 20220-7
Authors Lisby M, Olesen JR, Skouboe C, Krogh BO, Straub T, Boege F, Velmurugan S, Martensen PM, Andersen AH, Jayaram M, Westergaard O, Knudsen BR
Title Residues within the N-terminal domain of human topoisomerase I play a direct role in relaxation.
Related PDB
Related UniProtKB
[21]
Resource
Comments
Medline ID
PubMed ID 11809893
Journal Nucleic Acids Res
Year 2002
Volume 30
Pages 794-802
Authors Das A, Mandal C, Dasgupta A, Sengupta T, Majumder HK
Title An insight into the active site of a type I DNA topoisomerase from the kinetoplastid protozoan Leishmania donovani.
Related PDB
Related UniProtKB
[22]
Resource
Comments
Medline ID
PubMed ID 12439742
Journal Oncogene
Year 2002
Volume 21
Pages 7913-22
Authors Horie K, Tomida A, Sugimoto Y, Yasugi T, Yoshikawa H, Taketani Y, Tsuruo T
Title SUMO-1 conjugation to intact DNA topoisomerase I amplifies cleavable complex formation induced by camptothecin.
Related PDB
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID 12209008
Journal Proc Natl Acad Sci U S A
Year 2002
Volume 99
Pages 12102-7
Authors Lesher DT, Pommier Y, Stewart L, Redinbo MR
Title 8-Oxoguanine rearranges the active site of human topoisomerase I.
Related PDB 1lpq
Related UniProtKB
[24]
Resource
Comments
Medline ID
PubMed ID 12426403
Journal Proc Natl Acad Sci U S A
Year 2002
Volume 99
Pages 15387-92
Authors Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L
Title The mechanism of topoisomerase I poisoning by a camptothecin analog.
Related PDB 1k4s 1k4t
Related UniProtKB
[25]
Resource
Comments
Medline ID
PubMed ID 12533542
Journal J Biol Chem
Year 2003
Volume 278
Pages 12461-6
Authors Chrencik JE, Burgin AB, Pommier Y, Stewart L, Redinbo MR
Title Structural impact of the leukemia drug 1-beta-D-arabinofuranosylcytosine (Ara-C) on the covalent human topoisomerase I-DNA complex.
Related PDB 1nh3
Related UniProtKB
[26]
Resource
Comments
Medline ID
PubMed ID 12595561
Journal Nucleic Acids Res
Year 2003
Volume 31
Pages 1525-35
Authors Chillemi G, Fiorani P, Benedetti P, Desideri A
Title Protein concerted motions in the DNA-human topoisomerase I complex.
Related PDB
Related UniProtKB
[27]
Resource
Comments
Medline ID
PubMed ID 14594810
Journal J Biol Chem
Year 2004
Volume 279
Pages 2984-92
Authors Interthal H, Quigley PM, Hol WG, Champoux JJ
Title The role of lysine 532 in the catalytic mechanism of human topoisomerase I.
Related PDB 1r49
Related UniProtKB
[28]
Resource
Comments
Medline ID
PubMed ID 15165849
Journal J Mol Biol
Year 2004
Volume 339
Pages 773-84
Authors Chrencik JE, Staker BL, Burgin AB, Pourquier P, Pommier Y, Stewart L, Redinbo MR
Title Mechanisms of camptothecin resistance by human topoisomerase I mutations.
Related PDB 1rr8 1rrj
Related UniProtKB
[29]
Resource
Comments
Medline ID
PubMed ID 15801827
Journal J Med Chem
Year 2005
Volume 48
Pages 2336-45
Authors Staker BL, Feese MD, Cushman M, Pommier Y, Zembower D, Stewart L, Burgin AB
Title Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex.
Related PDB 1sc7 1seu 1t8i
Related UniProtKB
[30]
Resource
Comments
Medline ID
PubMed ID 16033260
Journal J Med Chem
Year 2005
Volume 48
Pages 4803-14
Authors Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M
Title Synthesis 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 PDB 1tl8
Related UniProtKB

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.

Created Updated
2004-04-27 2009-02-26