9T8F

Crystal structure of trabectedin bound to 10-mer duplex DNA

Summary for 9T8F

• Entry DOI: 10.2210/pdb9t8f/pdb
• Descriptor: DNA (5'-D(*CP*GP*AP*TP*GP*CP*AP*TP*CP*G)-3'), POTASSIUM ION, ECTEINASCIDIN 743, ... (4 entities in total)
• Functional Keywords: ecteinascidin, dna duplex, covalent bond, dna
• Biological source: DNA molecule
• Total number of polymer chains: 8
• Total formula weight: 28325.61

Authors

Darriere, T.,Ruiz, F.M.,Cuevas, C.,Fernandez-Tornero, C. (deposition date: 2025-11-12, release date: 2026-07-29, Last modification date: 2026-08-19)

Primary citation

Darriere, T.,Ruiz, F.M.,Martinez-Diez, M.,Ribeiro, M.L.,Cuevas, C.,Fernandez-Tornero, C.
The structures of ecteinascidin anticancer agents bound to DNA shed light on their mechanism of action.
Nucleic Acids Res., 54:-, 2026

PubMed Abstract: Ecteinascidins constitute a family of alkaloid compounds, originally isolated from marine tunicates, that exhibit strong antitumor activity. They act through binding to the DNA minor groove and forming covalent adducts with guanine residues. However, the limited availability of structural data restricts mechanistic insights into their mode of action and hampers the discovery of novel compounds. We report crystal structures of duplex DNA adducts with first-, second-, and third-generation ecteinascidins. The structures show that trabectedin, lurbinectedin, and PM54 bind through their shared A- and B-subunits, forming a covalent bond with the N2 atom of guanine and an extensive network of noncovalent interactions, leading to significant minor groove widening. In contrast, their C-subunit, which differs across the compounds, establishes distinct contacts with the modified strand that affect binding strength and sequence specificity. These structural findings, supported by Förster resonance energy transfer and biochemical assays, reveal the molecular determinants underlying differential sequence selectivity and reactivity. Our results provide a mechanistic framework for the anticancer activity of ecteinascidins and a structural basis to guide the design of next-generation analogues with improved therapeutic potential.

PubMed: 42522869
DOI: 10.1093/nar/gkag749

Experimental method

X-RAY DIFFRACTION (2.4 Å)