Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Human topoisomerase I (top1) is a key target for anticancer drugs.
• Existing drugs like camptothecins, indolocarbazoles, and indenoisoquinolines stabilize a top1-DNA covalent complex.
• Understanding the precise binding mechanism is crucial for developing new therapies.

Purpose of the Study:

• To determine the X-ray crystal structures of human top1-DNA complexes bound to diverse top1 poisons.
• To elucidate the common and unique binding interactions of different drug classes.
• To provide a basis for the rational design of novel anticancer agents targeting top1.

Main Methods:

• X-ray crystallography was used to obtain high-resolution structures.
• Complexes of human top1 with DNA were formed in the presence of camptothecin, indenoisoquinolines, and indolocarbazoles.
• Structural analysis focused on drug intercalation, interactions with top1 residues, and DNA binding.

Main Results:

• All three classes of top1 poisons share a common binding mode, intercalating into DNA at the cleavage site.
• A conserved interaction with Arg364 was observed across all drug classes.
• Specific, chemotype-dependent contacts with Asn352 and Glu356 were identified, involving alternative side-chain conformations.

Conclusions:

• The study reveals a conserved intercalative binding mode for diverse top1 poisons.
• Specific amino acid interactions explain how different drug structures stabilize the top1-DNA complex.
• These findings will facilitate the rational design of novel anticancer drugs targeting topoisomerase I.