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Human topoisomerase II beta in complex with DNA and etoposideHuman topoisomerase II beta in complex with DNA and etoposide

The purpose of this page is to explain a semisynthetic derivative of podophyllotoxin Chemical structure of podophyllotoxin (etoposide) that demonstrates antitumor activity by inhibiting DNA topoisomerase II, thereby inhibiting DNA re-ligation which lead to apoptosis of the cancer cell and also, to describe the mechanisms of resistance of etoposide. INTRODUCTION The research team led by professor Nei-li Chan and Tsai-kun Li at College of Medicine, National Taiwan University described the structural basis by which an anticancer drug etoposide kills cancer cells by interacting with its cellular targets human DNA topoisomerase type II . In the close-up representation of the cartoon-and-stick representation shows the insertion of two etoposide molecules into two cleavage sites [etoposide surrounded by orange mesh that represent active site (etoposide in red & grey representation), the DNA chain is in red and blue, and the magnesium is in green]. The neighboring magnesium’s are believed to be use at both the ATP binding domain and in the cleavage core. In the nucleotide binding pocket magnesium is known to contact all of the phosphate groups and it’s possible that the changes in magnesium can be linked to a diminishing in the nucleotide-binding pocket. ENZYME Type II topoisomerases (TOP2s) are abundant enzymes that play an essential role in replication and transcription and are important targets for cancer chemotherapeutic drugs. These enzymes briefly cleave a pair of opposing phosphodiester bonds four base pairs apart, generating a TOP2-DNA cleavage complex. TOP2’s DNA cleavage activity is usually referred to as a double-edged sword; failure to reseal the enzyme-mediated DNA break can lead to cell death. Several potent anticancer drugs, such as , and (all in green), exploit this harmful aspect of TOP2 and promote the formation of cytotoxic DNA lesions by increasing the stability level of cleavage complexes. In this paper, the researchers reported on the crystal structure of a large fragment of type II human topoisomerases β (hTOP2β core) complexed to DNA and to the anticancer drug etoposide to reveal structural details of drug-induced stabilization of a cleavage complex ]] 2. Changes in target proteins: This mechanism relates directly to the target enzyme; Either low enzyme levels or altered sensitivity of the enzyme for the drug confers resistance to that drug. This mechanism also confers a form of multidrug resistance; in that resistance to one topoisomerase II inhibitor through decreased or altered topoisomerase activity generally translates into resistance to most other topoisomerase II inhibitors. Mutation of Glycine at position 465 According to earlier experiments, the glycine at position 465 in this structure is proposed to lie very close to the cleavage site and it’s is therefore expected to be involved in ATP hydrolysis. So the change of residue 465 from to a more negatively charged is determined to create some localized hydrogen bonding at the backbone that can potentially alter the conformation of the enzyme (this change is determined to alter the charge interactions involved in binding site).

spinqualitylabelsall models Structure of the human topoisomeraseIIbcore-DNA cleavage complex stabilized by the anticancer drug etoposide. (PDB entry 3QX3) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image