1TL8

Human DNA topoisomerase I (70 kDa) in complex with the indenoisoquinoline AI-III-52 and covalent complex with a 22 base pair DNA duplex

Summary for 1TL8

• Entry DOI: 10.2210/pdb1tl8/pdb
• Related: 1K4t
• Descriptor: 5'-D(*AP*AP*AP*AP*AP*GP*AP*CP*TP*T)-3', 5'-D(*(TPC)P*GP*AP*AP*AP*AP*AP*TP*TP*TP*TP*T)-3', 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', ... (5 entities in total)
• Functional Keywords: complex (isomerase-dna), dna, topoisomerase i, drug, poison, idenoisoquinoline, isomerase-dna complex, isomerase/dna
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus, nucleolus: P11387
• Total number of polymer chains: 4
• Total formula weight: 84038.30

Authors

Ioanoviciu, A.,Antony, S.,Pommier, Y.,Staker, B.L.,Stewart, L.,Cushman, M. (deposition date: 2004-06-09, release date: 2005-06-21, Last modification date: 2024-11-06)

Primary citation

Ioanoviciu, A.,Antony, S.,Pommier, Y.,Staker, B.L.,Stewart, L.,Cushman, M.
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, 2005

PubMed 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.

PubMed: 16033260
DOI: 10.1021/jm050076b

Experimental method

X-RAY DIFFRACTION (3.1 Å)