1k4s
From Proteopedia
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HUMAN DNA TOPOISOMERASE I IN COVALENT COMPLEX WITH A 22 BASE PAIR DNA DUPLEX
Contents |
Overview
We report the x-ray crystal structure of human topoisomerase I covalently, joined to double-stranded DNA and bound to the clinically approved, anticancer agent Topotecan. Topotecan mimics a DNA base pair and binds at, the site of DNA cleavage by intercalating between the upstream (-1) and, downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding, to the enzyme-substrate complex, Topotecan acts as an uncompetitive, inhibitor. The structure can explain several of the known, structure-activity relationships of the camptothecin family of anticancer, drugs and suggests that there are at least two classes of mutations that, can produce a drug-resistant enzyme. The first class includes changes to, residues that contribute to direct interactions with the drug, whereas a, second class would alter interactions with the DNA and thereby destabilize, the drug-binding site.
Disease
Known disease associated with this structure: DNA topoisomerase I, camptothecin-resistant OMIM:[126420]
About this Structure
1K4S is a Single protein structure of sequence from Homo sapiens. Active as DNA topoisomerase, with EC number 5.99.1.2 Full crystallographic information is available from OCA.
Reference
The mechanism of topoisomerase I poisoning by a camptothecin analog., Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L, Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15387-92. Epub 2002 Nov 8. PMID:12426403
Page seeded by OCA on Mon Nov 12 17:47:14 2007
