PDBsum entry 1tl8

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protein dna_rna ligands links
Isomerase/DNA PDB id
Protein chain
565 a.a. *
* Residue conservation analysis
PDB id:
Name: Isomerase/DNA
Title: Human DNA topoisomerase i (70 kda) in complex with the indenoisoquinoline ai-iii-52 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( (Tpc)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 Gp 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)
3.10Å     R-factor:   0.229     R-free:   0.305
Authors: A.Ioanoviciu,S.Antony,Y.Pommier,B.L.Staker,L.Stewart, M.Cushman
Key ref: A.Ioanoviciu et al. (2005). 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. J Med Chem, 48, 4803-4814. PubMed id: 16033260 DOI: 10.1021/jm050076b
09-Jun-04     Release date:   21-Jun-05    
Go to PROCHECK summary

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

 Enzyme reactions 
   Enzyme class: E.C.  - Dna topoisomerase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP-independent breakage of single-stranded DNA, followed by passage and rejoining.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     chromosome   1 term 
  Biological process     DNA topological change   1 term 
  Biochemical function     DNA binding     3 terms  


DOI no: 10.1021/jm050076b J Med Chem 48:4803-4814 (2005)
PubMed id: 16033260  
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.
A.Ioanoviciu, S.Antony, Y.Pommier, B.L.Staker, L.Stewart, M.Cushman.
Several norindenoisoquinolines substituted with methoxy or methylenedioxy groups have been prepared and their anticancer properties evaluated in cancer cell cultures and in topoisomerase I inhibition assays. 2,3-Dimethoxy-8,9-methylenedioxy-11H-indeno[1,2-c]isoquinoline hydrochloride (14) is a strong topoisomerase I inhibitor and also displays very high cytotoxicity in the NCI cancer cell culture screen (mean graph midpoint of 50 nM). The X-ray crystal structure of norindenoisoquinoline 14 in complex with topoisomerase I and DNA has been solved, providing insight into the structure-activity relationships within this class of new anticancer agents. The number and position of the norindenoisoquinoline substituents have a significant influence on biological activity and demonstrate that substitution on the nitrogen atom is not an absolute requirement for the antitumor effect of the indenoisoquinolines. Removal of the 11-keto group from the lead compound 1 and replacement of the N-alkyllactam with an unsubstituted pyridine ring causes the indenoisoquinoline ring system to flip over in the DNA-enzyme-inhibitor ternary complex. This allows the nitrogen atom to assume the hydrogen bond acceptor role of the 11-keto group, resulting in hydrogen bonding to Arg364.

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.  
21414693 M.Zheng, Y.Yang, M.Zhao, X.Zhang, J.Wu, G.Chen, L.Peng, Y.Wang, and S.Peng (2011).
A class of novel N-isoquinoline-3-carbonyl-L-amino acid benzylesters: synthesis, anti-tumor evaluation and 3D QSAR analysis.
  Eur J Med Chem, 46, 1672-1681.  
20677319 S.Boonya-Udtayan, N.Yotapan, C.Woo, C.J.Bruns, S.Ruchirawat, and N.Thasana (2010).
Synthesis and biological activities of azalamellarins.
  Chem Asian J, 5, 2113-2123.  
20534341 Y.Pommier, E.Leo, H.Zhang, and C.Marchand (2010).
DNA topoisomerases and their poisoning by anticancer and antibacterial drugs.
  Chem Biol, 17, 421-433.  
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.  
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.  
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.  
18927559 T.S.Dexheimer, and Y.Pommier (2008).
DNA cleavage assay for the identification of topoisomerase I inhibitors.
  Nat Protoc, 3, 1736-1750.  
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.  
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.  
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.  
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.  
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.  
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.  
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.  
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.