1tl8

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spinqualitylabelsall models 1tl8, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[126420]

About this Structure

1TL8 is a Single protein structure of sequence from Homo sapiens with AI3 as ligand. Active as DNA topoisomerase, with EC number 5.99.1.2 Full crystallographic information is available from OCA.

Reference

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., Ioanoviciu A, Antony S, Pommier Y, Staker BL, Stewart L, Cushman M, J Med Chem. 2005 Jul 28;48(15):4803-14. PMID:16033260

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