PDBsum entry 1sc7

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protein dna_rna ligands links
Isomerase/DNA PDB id
Jmol PyMol
Protein chain
567 a.a. *
* Residue conservation analysis
PDB id:
Name: Isomerase/DNA
Title: Human DNA topoisomerase i (70 kda) in complex with the indenoisoquinoline mj-ii-38 and covalent complex with a 22 base pair DNA duplex
Structure: 5'-d( Ap Ap Ap Ap Ap Gp Ap Cp Tp T)-3'. Chain: b. Engineered: yes. 5'-d( (Tgp)p Gp Ap Ap Ap Ap Ap Tp Tp Tp Tp T)-3'. Chain: c. Engineered: yes. 5'- d( Ap Ap Ap Ap Ap Tp Tp Tp Tp Tp Cp Cp Ap Ap Gp Tp Cp Tp Tp Tp Tp T)-3'.
Source: Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Gene: top1. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Biol. unit: Tetramer (from PQS)
3.00Å     R-factor:   0.233     R-free:   0.285
Authors: B.L.Staker,M.D.Feese,M.Cushman,Y.Pommier,D.Zembower, L.Stewart,A.B.Burgin
Key ref: B.L.Staker et al. (2005). Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. J Med Chem, 48, 2336-2345. PubMed id: 15801827 DOI: 10.1021/jm049146p
11-Feb-04     Release date:   19-Apr-05    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P11387  (TOP1_HUMAN) -  DNA topoisomerase 1
765 a.a.
567 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     chromosome   1 term 
  Biological process     DNA topological change   1 term 
  Biochemical function     DNA binding     2 terms  


DOI no: 10.1021/jm049146p J Med Chem 48:2336-2345 (2005)
PubMed id: 15801827  
Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex.
B.L.Staker, M.D.Feese, M.Cushman, Y.Pommier, D.Zembower, L.Stewart, A.B.Burgin.
Human topoisomerase I (top1) is the molecular target of a diverse set of anticancer compounds, including the camptothecins, indolocarbazoles, and indenoisoquinolines. These compounds bind to a transient top1-DNA covalent complex and inhibit the resealing of a single-strand nick that the enzyme creates to relieve superhelical tension in duplex DNA. (Hertzberg, R. P.; et al. Biochem. 1989, 28, 4629-4638. Hsiang, Y. H.; et al. J. Biol. Chem 1985, 260, 14873-14878. Champoux, J. J. Annu. Rev. Biochem. 2001, 70, 369-413. Stewart, L.; et al. Science 1998, 729, 1534-1541.) We report the X-ray crystal structures of the human top1-DNA complex bound with camptothecin and representative members of the indenoisoquinoline and indolocarbazole classes of top1 poisons. The planar nature of all three structurally diverse classes allows them to intercalate between DNA base pairs at the site of single-strand cleavage. All three classes of compounds have a free electron pair near Arg364, a residue that if mutated confers resistance to all three classes of drugs. The common intercalative binding mode is augmented by unexpected chemotype-specific contacts with amino acid residues Asn352 and Glu356, which adopt alternative side-chain conformations to accommodate the bound compounds. These new X-ray structures explain how very different molecules can stabilize top1-DNA covalent complexes and will aid the rational design of completely novel structural classes of anticancer drugs.

Literature references that cite this PDB file's key reference

  PubMed id Reference
22173432 Y.Pommier, and C.Marchand (2012).
Interfacial inhibitors: targeting macromolecular complexes.
  Nat Rev Drug Discov, 11, 25-36.  
21463912 W.Liu, L.Zhu, W.Guo, C.Zhuang, Y.Zhang, C.Sheng, P.Cheng, J.Yao, W.Wang, G.Dong, S.Wang, Z.Miao, and W.Zhang (2011).
Synthesis and biological evaluation of novel 7-acyl homocamptothecins as Topoisomerase I inhibitors.
  Eur J Med Chem, 46, 2408-2414.  
20485741 B.A.Neto, A.A.Lapis, F.S.Mancilha, E.L.Batista, P.A.Netz, F.Rominger, L.A.Basso, D.S.Santos, and J.Dupont (2010).
On the selective detection of duplex deoxyribonucleic acids by 2,1,3-benzothiadiazole fluorophores.
  Mol Biosyst, 6, 967-975.  
21069656 C.Samorì, G.L.Beretta, G.Varchi, A.Guerrini, S.Di Micco, S.Basili, G.Bifulco, R.Riccio, S.Moro, E.Bombardelli, F.Zunino, and G.Fontana (2010).
Structure-activity relationship study of 16‚ÄČa-thiocamptothecins: an integrated in vitro and in silico approach.
  ChemMedChem, 5, 2006-2015.  
20187656 M.R.Stahley, and J.T.Stivers (2010).
Mechanism and specificity of DNA strand exchange catalyzed by vaccinia DNA topoisomerase type I.
  Biochemistry, 49, 2786-2795.  
20636260 O.Y.Susova, A.A.Ivanov, S.S.Morales Ruiz, E.A.Lesovaya, A.V.Gromyko, S.A.Streltsov, and A.L.Zhuze (2010).
Minor groove dimeric bisbenzimidazoles inhibit in vitro DNA binding to eukaryotic DNA topoisomerase I.
  Biochemistry (Mosc), 75, 695-701.  
20947527 T.Cheng, Y.Wang, and S.H.Bryant (2010).
Investigating the correlations among the chemical structures, bioactivity profiles and molecular targets of small molecules.
  Bioinformatics, 26, 2881-2888.  
20155916 Y.Song, Z.Shao, T.S.Dexheimer, E.S.Scher, Y.Pommier, and M.Cushman (2010).
Structure-based design, synthesis, and biological studies of new anticancer norindenoisoquinoline topoisomerase I inhibitors.
  J Med Chem, 53, 1979-1989.  
19851285 B.B.Das, S.Antony, S.Gupta, T.S.Dexheimer, C.E.Redon, S.Garfield, Y.Shiloh, and Y.Pommier (2009).
Optimal function of the DNA repair enzyme TDP1 requires its phosphorylation by ATM and/or DNA-PK.
  EMBO J, 28, 3667-3680.  
19756309 H.T.Chiu, Y.C.Lin, M.N.Lee, Y.L.Chen, M.S.Wang, and C.C.Lai (2009).
Biochemical characterization and substrate specificity of the gene cluster for biosyntheses of K-252a and its analogs by in vitro heterologous expression system of Escherichia coli.
  Mol Biosyst, 5, 1192-1203.  
19424733 K.G.Byler, C.Wang, and W.N.Setzer (2009).
Quinoline alkaloids as intercalative topoisomerase inhibitors.
  J Mol Model, 15, 1417-1426.  
19783447 M.A.Cinelli, B.Cordero, T.S.Dexheimer, Y.Pommier, and M.Cushman (2009).
Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: investigating the hypothesis of shared structure-activity relationships.
  Bioorg Med Chem, 17, 7145-7155.  
19106140 N.M.Baker, R.Rajan, and A.Mondragón (2009).
Structural studies of type I topoisomerases.
  Nucleic Acids Res, 37, 693-701.  
18824603 R.P.Bakshi, D.Sang, A.Morrell, M.Cushman, and T.A.Shapiro (2009).
Activity of indenoisoquinolines against African trypanosomes.
  Antimicrob Agents Chemother, 53, 123-128.  
19383846 Y.Pommier, and M.Cushman (2009).
The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives.
  Mol Cancer Ther, 8, 1008-1014.  
19476377 Y.Pommier (2009).
DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition.
  Chem Rev, 109, 2894-2902.  
19089006 Z.F.Chen, Y.C.Liu, L.M.Liu, H.S.Wang, S.H.Qin, B.L.Wang, H.D.Bian, B.Yang, H.K.Fun, H.G.Liu, H.Liang, and C.Orvig (2009).
Potential new inorganic antitumour agents from combining the anticancer traditional Chinese medicine (TCM) liriodenine with metal ions, and DNA binding studies.
  Dalton Trans, (), 262-272.  
18157856 F.Animati, M.Berettoni, M.Bigioni, M.Binaschi, P.Felicetti, L.Gontrani, O.Incani, A.Madami, E.Monteagudo, L.Olivieri, S.Resta, C.Rossi, and A.Cipollone (2008).
Synthesis, biological evaluation, and molecular modeling studies of rebeccamycin analogues modified in the carbohydrate moiety.
  ChemMedChem, 3, 266-279.  
18765473 G.Chillemi, I.D'Annessa, P.Fiorani, C.Losasso, P.Benedetti, and A.Desideri (2008).
Thr729 in human topoisomerase I modulates anti-cancer drug resistance by altering protein domain communications as suggested by molecular dynamics simulations.
  Nucleic Acids Res, 36, 5645-5651.  
18318502 J.E.Deweese, A.B.Burgin, and N.Osheroff (2008).
Using 3'-bridging phosphorothiolates to isolate the forward DNA cleavage reaction of human topoisomerase IIalpha.
  Biochemistry, 47, 4129-4140.  
18630891 M.A.Cinelli, A.Morrell, T.S.Dexheimer, E.S.Scher, Y.Pommier, and M.Cushman (2008).
Design, synthesis, and biological evaluation of 14-substituted aromathecins as topoisomerase I inhibitors.
  J Med Chem, 51, 4609-4619.  
18805512 M.Christmann, M.T.Tomicic, C.Gestrich, W.P.Roos, V.A.Bohr, and B.Kaina (2008).
WRN protects against topo I but not topo II inhibitors by preventing DNA break formation.
  DNA Repair (Amst), 7, 1999-2009.  
18056711 M.van der Merwe, and M.A.Bjornsti (2008).
Mutation of gly721 alters DNA topoisomerase I active site architecture and sensitivity to camptothecin.
  J Biol Chem, 283, 3305-3315.  
18927559 T.S.Dexheimer, and Y.Pommier (2008).
DNA cleavage assay for the identification of topoisomerase I inhibitors.
  Nat Protoc, 3, 1736-1750.  
18451142 X.Chen, S.Zhong, X.Zhu, B.Dziegielewska, T.Ellenberger, G.M.Wilson, A.D.MacKerell, and A.E.Tomkinson (2008).
Rational design of human DNA ligase inhibitors that target cellular DNA replication and repair.
  Cancer Res, 68, 3169-3177.  
18636761 Y.Song, and M.Cushman (2008).
The binding orientation of a norindenoisoquinoline in the topoisomerase I-DNA cleavage complex is primarily governed by pi-pi stacking interactions.
  J Phys Chem B, 112, 9484-9489.  
17072654 A.Lauria, M.Ippolito, and A.M.Almerico (2007).
Molecular docking approach on the Topoisomerase I inhibitors series included in the NCI anti-cancer agents mechanism database.
  J Mol Model, 13, 393-400.  
17402722 A.Morrell, M.S.Placzek, J.D.Steffen, S.Antony, K.Agama, Y.Pommier, and M.Cushman (2007).
Investigation of the lactam side chain length necessary for optimal indenoisoquinoline topoisomerase I inhibition and cytotoxicity in human cancer cell cultures.
  J Med Chem, 50, 2040-2048.  
17886246 C.Hansch, and R.P.Verma (2007).
20-(S)-Camptothecin Analogues as DNA Topoisomerase I Inhibitors: A QSAR Study.
  ChemMedChem, 2, 1807-1813.  
17434318 C.Punchihewa, J.Dai, M.Carver, and D.Yang (2007).
Human topoisomerase I C-terminal domain fragment containing the active site tyrosine is a molten globule: implication for the formation of competent productive complex.
  J Struct Biol, 159, 111-121.  
18254239 I.Choi, C.Kim, and S.Choi (2007).
Binding mode analysis of topoisomerase inhibitors, 6-arylamino-7-chloro-quinazoline-5,8-diones, within the cleavable complex of human topoisomerase I and DNA.
  Arch Pharm Res, 30, 1526-1535.  
17873060 K.S.Ryan, A.R.Howard-Jones, M.J.Hamill, S.J.Elliott, C.T.Walsh, and C.L.Drennan (2007).
Crystallographic trapping in the rebeccamycin biosynthetic enzyme RebC.
  Proc Natl Acad Sci U S A, 104, 15311-15316.
PDB codes: 2r0c 2r0g 2r0p
17095016 Q.A.Khan, and D.S.Pilch (2007).
Topoisomerase I-mediated DNA cleavage induced by the minor groove-directed binding of bibenzimidazoles to a distal site.
  J Mol Biol, 365, 561-569.  
17827209 R.F.Frøhlich, C.Veigaard, F.F.Andersen, A.K.McClendon, A.C.Gentry, A.H.Andersen, N.Osheroff, T.Stevnsner, and B.R.Knudsen (2007).
Tryptophane-205 of human topoisomerase I is essential for camptothecin inhibition of negative but not positive supercoil removal.
  Nucleic Acids Res, 35, 6170-6180.  
17393079 Y.Zu, C.Gao, W.Wang, F.Yang, Y.Liu, M.Wang, and Y.Zhao (2007).
Characteristics of the microbial community in rhizosphere of Camptotheca acuminata cultured with exotic invasive plant Eupatorium adenophorum.
  Sci China C Life Sci, 50, 22-30.  
17181156 A.Morrell, S.Antony, G.Kohlhagen, Y.Pommier, and M.Cushman (2006).
A systematic study of nitrated indenoisoquinolines reveals a potent topoisomerase I inhibitor.
  J Med Chem, 49, 7740-7753.  
16368685 A.Patel, S.Shuman, and A.Mondragón (2006).
Crystal structure of a bacterial type IB DNA topoisomerase reveals a preassembled active site in the absence of DNA.
  J Biol Chem, 281, 6030-6037.
PDB code: 2f4q
16505102 C.Marchand, S.Antony, K.W.Kohn, M.Cushman, A.Ioanoviciu, B.L.Staker, A.B.Burgin, L.Stewart, and Y.Pommier (2006).
A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex.
  Mol Cancer Ther, 5, 287-295.  
17119643 C.Sánchez, C.Méndez, and J.A.Salas (2006).
Indolocarbazole natural products: occurrence, biosynthesis, and biological activity.
  Nat Prod Rep, 23, 1007-1045.  
16905549 H.Takemura, V.A.Rao, O.Sordet, T.Furuta, Z.H.Miao, L.Meng, H.Zhang, and Y.Pommier (2006).
Defective Mre11-dependent activation of Chk2 by ataxia telangiectasia mutated in colorectal carcinoma cells in response to replication-dependent DNA double strand breaks.
  J Biol Chem, 281, 30814-30823.  
16885024 K.Perry, Y.Hwang, F.D.Bushman, and G.D.Van Duyne (2006).
Structural basis for specificity in the poxvirus topoisomerase.
  Mol Cell, 23, 343-354.
PDB codes: 2h7f 2h7g
17034134 M.Nagarajan, A.Morrell, A.Ioanoviciu, S.Antony, G.Kohlhagen, K.Agama, M.Hollingshead, Y.Pommier, and M.Cushman (2006).
Synthesis and evaluation of indenoisoquinoline topoisomerase I inhibitors substituted with nitrogen heterocycles.
  J Med Chem, 49, 6283-6289.  
16990249 P.Fiorani, G.Chillemi, C.Losasso, S.Castelli, and A.Desideri (2006).
The different cleavage DNA sequence specificity explains the camptothecin resistance of the human topoisomerase I Glu418Lys mutant.
  Nucleic Acids Res, 34, 5093-5100.  
16846801 R.Balaña-Fouce, C.M.Redondo, Y.Pérez-Pertejo, R.Díaz-González, and R.M.Reguera (2006).
Targeting atypical trypanosomatid DNA topoisomerase I.
  Drug Discov Today, 11, 733-740.  
16480276 X.Xiao, S.Antony, Y.Pommier, and M.Cushman (2006).
Total synthesis and biological evaluation of 22-hydroxyacuminatine.
  J Med Chem, 49, 1408-1412.  
16990856 Y.Pommier (2006).
Topoisomerase I inhibitors: camptothecins and beyond.
  Nat Rev Cancer, 6, 789-802.  
16891172 Y.Pommier, J.M.Barcelo, V.A.Rao, O.Sordet, A.G.Jobson, L.Thibaut, Z.H.Miao, J.A.Seiler, H.Zhang, C.Marchand, K.Agama, J.L.Nitiss, and C.Redon (2006).
Repair of topoisomerase I-mediated DNA damage.
  Prog Nucleic Acid Res Mol Biol, 81, 179-229.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.