1K4T

HUMAN DNA TOPOISOMERASE I (70 KDA) IN COMPLEX WITH THE POISON TOPOTECAN AND COVALENT COMPLEX WITH A 22 BASE PAIR DNA DUPLEX

Summary for 1K4T

• Entry DOI: 10.2210/pdb1k4t/pdb
• Related: 1A31 1A35 1A36 1K4S
• Descriptor: 5'-D(*AP*AP*AP*AP*AP*GP*AP*CP*TP*T)-3', 5'-D(*(TGP)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*CP*AP*AP*GP*TP*CP*TP*TP*TP*TP*T)-3', ... (9 entities in total)
• Functional Keywords: complex (isomerase-dna), dna, topoisomerase i, drug, poison, isomerase-dna complex, isomerase/dna
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus, nucleolus: P11387
• Total number of polymer chains: 4
• Total formula weight: 84971.68

Authors

Staker, B.L.,Hjerrild, K.,Feese, M.D.,Behnke, C.A.,Burgin Jr., A.B.,Stewart, L.J. (deposition date: 2001-10-08, release date: 2002-12-04, Last modification date: 2024-10-30)

Primary citation

Staker, B.L.,Hjerrild, K.,Feese, M.D.,Behnke, C.A.,Burgin Jr., A.B.,Stewart, L.J.
The mechanism of topoisomerase I poisoning by a camptothecin analog
Proc.Natl.Acad.Sci.USA, 99:15387-15392, 2002

PubMed Abstract: 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.

PubMed: 12426403
DOI: 10.1073/pnas.242259599

Experimental method

X-RAY DIFFRACTION (2.1 Å)