Opioid Receptor structures of integrase with its viral substrates have revealed the trapping

target eukaryotic topoisomerases via a comparable mechanism; at the time, it was proposed that the drugs were trapping topoisomerase cleavage complexes by forming ternary complexes with a drug molecule bound at the interface of the enzymes and the cleaved DNA4. It took about 10 years to validate the ternary complex hypothesis, which was achieved when the crystal structure Ubiquinone of the TOP1 ternary complex was solved with topotecan intercalated in the cleaved DNA and specifically bound to TOP1 . Soon after, the ternary complex structure was confirmed for the natural alkaloid camptothecin and the indenoisoquinolines, the non camptothecin inhibitors of TOP1, which are currently in clinical trials6,7.
We proposed the interfacial inhibitor concept because of the common mechanistic priple underlying the mechanism of action of distantly related natural drugs8,9. Camptothecin and brefeldin A served as the landmark Opioid Receptor examples, each targeting different macromolecular machines: camptothecin targets TOP1 DNA complexes, whereas brefeldin A targets the protein protein complex formed by ADP ribosylation factor and guanine nucleotide exchange factor8. The macromolecular structures of natural inhibitors have been extensively analysed in the literature; this has extended the relevance of the interfacial inhibitor concept to a range of drugs and molecular machines, luding cyclosporine, tacrolimus , forskolin, fusicoccin, rapamycin, colchicine, va alkaloids, paclitaxel and α‑amanitin8. Se then, antibiotics have been shown to act as interfacial inhibitors for bacterial type II topoisomerases10 12.
The interfacial inhibition mechanism has recently been extended to purely synthetic compounds such as the anti AIDS drugs that target the HIV integrase viral DNA complexes. Stunning co crystal structures of integrase with its viral substrates have revealed the trapping of the integrase DNA complex as the drugs bind at its horticulture interface13 15. The interfacial hypothesis for the targeting of eukaryotic TOP2 by etoposide has also recently been confirmed16, as discussed below. Examples of interfacial inhibitors Several drug classes and targets of interfacial inhibitors are listed in TABLE 1. Below, we describe several examples of interfacial inhibitors, to clarify the concept of interfacial inhibition. Camptothecins and non camptothecin anticancer TOP1 inhibitors.
Topoisomerases belong to a large family of enzymes that regulate the topology of DNA without changing its primary sequence. They are ubiquitously expressed in eukaryotes, prokaryotes and archaea, and are also encoded by some viruses. Topoisomerases can be viewed as ’3 in 1 machines’ because a single enzyme performs three consecutive reactions. First, a topoisomerase cleaves the DNA backbone ; second, it allows changes in DNA supercoils ; and third, it re ligates the cleaved DNA . Topoisomerases are classified as type I or type II, depending on whether they cleave one or both DNA strands in concert, respectively17. The human genome contains six topoisomerase genes that encode two type IB enzymes ), two type IA enzymes and two type IIA enzymes . TOP1MT is only found in vertebrates. It is encoded in the nucleus but only acts on mitochondrial DNA4. The bacterium Escherichia coli encodes.

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