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1k4t
From Proteopedia
| 1k4t, resolution 2.10Å () | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Sites: | , , and | ||||||||
| Ligands: | , , , | ||||||||
| Non-Standard Residues: | , | ||||||||
| Activity: | DNA topoisomerase, with EC number 5.99.1.2 | ||||||||
| Related: | 1a35, 1a31, 1a36, 1k4s | ||||||||
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
Contents |
HUMAN DNA TOPOISOMERASE I (70 KDA) IN COMPLEX WITH THE POISON TOPOTECAN AND COVALENT COMPLEX WITH A 22 BASE PAIR DNA DUPLEX
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.
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
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
About this Structure
1k4t is a 4 chain structure of Topoisomerase with sequence from Homo sapiens. Full crystallographic information is available from OCA.
See Also
Reference
- Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15387-92. Epub 2002 Nov 8. PMID:12426403 doi:10.1073/pnas.242259599
Categories: DNA topoisomerase | Homo sapiens | Behnke, C A. | Burgin, A B. | Feese, M D. | Hjerrild, K. | Staker, B L. | Stewart, L J. | Dna | Drug | Poison | Topoisomerase i
