PDBsum entry: 1tl8

Isomerase/DNA

PDB id: 1tl8

Contents

Protein chain

565 a.a. *

DNA/RNA

Ligands

AI3

* Residue conservation analysis

PDB id:

1tl8

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)

Resolution:

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

Date:

09-Jun-04 Release date: 21-Jun-05

Protein chain

P11387  (TOP1_HUMAN) -  DNA topoisomerase 1

Seq: 765 a.a.

Struc: 565 a.a.

Enzyme reactions

• Enzyme class: E.C.5.99.1.2 - Dna topoisomerase.
• Reaction: ATP-independent breakage of single-stranded DNA, followed by passage and rejoining.

 Gene Ontology (GO) functional annotation 

• Cellular component: chromosome (1 term)
• Biological process: DNA topological change (2 terms)
• 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.

ABSTRACT

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.