Abstact

Trabectedin is a DNA-binding natural product with potent anticancer activities. Trabectedin is used clinically worldwide to treat soft tissue sarcomas and ovarian cancer. A crystal structure of trabectedin in complex with DNA has been elusive. This study describes a crystal structure of a covalent trabectedin-DNA complex at a resolution of 1.8 A. The structure demonstrates the conformation and position of the trabectedin adduct in the minor groove of DNA, revealing numerous drug-DNA interactions, conformational differences in DNA and trabectedin caused by their binding. The structure also explains the previously observed DNA sequence preference of trabectedin. This crystal structure will be useful for further inquiry into the mechanism of action of trabectedin and for the rational design of improved trabectedin analogues.