TCR Pathway have also been successfully co crystallized with the bacterial

between the base pairs flanking the cleavage sites generated by a topoisomerase28,29. Sodium Danshensu This hypothesis was derived from the observation that each chemical class of inhibitors selectively traps TOP2 at different sites30,31. Furthermore, sequencing a large collection of drug induced TOP2 cleavage sites revealed that these differences are defined by the base pairs that flank those sites32. Namely, doxorubicin, daunorubicin, epirubicin and other anthracyclines trap TOP2 cleavage complexes with an adenine at the 3′ end of the break 28,33, whereas amsacrine preferentially traps the A+1 sites; etoposide, teniposide and mitoxantrone preferentially trap TOP2 cleavage complexes at C–1 sites29,34. Chan and colleagues16 have successfully co crystallized etoposide in a ternary complex with TOP2β, based on the preference of etoposide and teniposide for the trapping of TOP2 at the C–1 base32.
The crystal structure confirms the prediction29 that the etoposide drug molecule stacks against the C–1 or G+5 base pair and forms a network of hydrogen bonds and van der Waals interactions with TOP2 . Furthermore, TCR Pathway the same group has successfully co crystallized mitoxantrone in the TOP2 cleavage complex and demonstrated that mitoxantrone has a similar mechanism of action to etoposide . Quinolone antibiotics: inhibitors of bacterial type II topoisomerases. Antibiotics have also been successfully co crystallized with the bacterial type II topoisomerases topoisomerase IV10,11 and DNA gyrase12, and have been shown to act as interfacial inhibitors.
Because topoisomerase IV and DNA gyrase are essential for bacterial replication and are sufficiently horticulture different from the eukaryotic TOP2α and TOP2β enzymes, which are insensitive to the antibiotics, bacterial type II topoisomerases are prime targets for antibiotics4. Moreover, the same antibacterial topoisomerase inhibitors usually target both DNA gyrase and topoisomerase IV owing to the high structural similarities between the two prokaryotic enzymes4. Quinolone antibiotics represent the archetype of bacterial type II topoisomerase poisons. They were introduction of a fluorine atom in their structure broadened their antibacterial spectrum. Several generations of fluoroquinolone derivatives have led to some of the most potent antibiotics available to date, such as ciprofloxacin and levofloxacin4 .
Similarly to other topoisomerase poisons, fluoroquinolones trap bacterial type II topoisomerases in a stabilized cleavage complex by stacking between the base pairs flanking the cleavage sites at the interface of the parC and parE subunits of topoisomerase IV10,35 . In the context of DNA gyrase and interfacial inhibition, it is relevant to mention the ccd operon of the F plasmid of E. coli, which represents an archetype of the toxin–antitoxin modules that are present in many bacteria and archaea, and function as biological interfacial inhibitors36. These plasmid encoded toxin–antitoxin systems may be used for the development of novel antibiotics37. The ccd operon on the F plasmid encodes two proteins: the toxin CcdB and its antitoxin CcdA. CcdB poisons DNA gyrase by binding as a homodimer to both subunits A of DNA gyrase in the centre of the heterodimer, keeping the gyrase in an open conformation with the cleaved DNA38.