8XIC

Structure of Trioxacarcin A covalently bound to guanosine-2'-fluorinated d(AACCGGTT)2

Summary for 8XIC

• Entry DOI: 10.2210/pdb8xic/pdb
• Descriptor: DNA (5'-D(*AP*AP*CP*CP*2''F-GP*2''F-GP*TP*T)-3'), Trioxacarcin A, bound form (2 entities in total)
• Functional Keywords: complex, dna alkylation, base mismatch, dna
• Biological source: DNA molecule
• Total number of polymer chains: 2
• Total formula weight: 6522.97

Authors

Gao, R.Q.,Cao, C.,Tang, G.L. (deposition date: 2023-12-19, release date: 2024-12-04, Last modification date: 2024-12-11)

Primary citation

Gao, R.Q.,Hu, X.D.,Zhou, Q.,Hou, X.F.,Cao, C.,Tang, G.L.
Different DNA Binding and Damage Mode between Anticancer Antibiotics Trioxacarcin A and LL-D49194 alpha 1.
Jacs Au, 4:3641-3648, 2024

PubMed Abstract: Trioxacarcin A (TXN) is a highly potent cytotoxic antibiotic with remarkable structural complexity. The crystal structure of TXN bound to double-stranded DNA (dsDNA) suggested that the TXN interaction might depend on positions of two sugar subunits on the minor and major grooves of dsDNA. LL-D49194α1 (LLD) is a TXN analogue bearing the same polycyclic polyketide scaffold with a distinct glycosylation pattern. Although LLD was in a phase I clinical trial, how LLD binds to dsDNA remains unclear. Here, we solved the solution structures at high resolutions of palindromic 2″-fluorine-labeled guanine-containing duplex d(AACCGGTT) and of its stable LLD and TXN covalently bound complexes. Combined with biochemical assays, we found that TXN-alkylated dsDNA would tend to keep DNA helix conformation, while LLD-alkylated dsDNA lost its stability more than TXN-alkylated dsDNA, leading to dsDNA denaturation. Thus, despite lower cytotoxicity in vitro, the differences of sugar substitutions in LLD caused greater DNA damage than TXN, thereby bringing about a completely new biological effect.

PubMed: 39328742
DOI: 10.1021/jacsau.4c00611

Experimental method

SOLUTION NMR