1qzr
From Proteopedia
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CRYSTAL STRUCTURE OF THE ATPASE REGION OF SACCHAROMYCES CEREVISIAE TOPOISOMERASE II BOUND TO ICRF-187 (DEXRAZOXANE)
Overview
Type IIA topoisomerases both manage the topological state of chromosomal, DNA and are the targets of a variety of clinical agents., Bisdioxopiperazines are anticancer agents that associate with ATP-bound, eukaryotic topoisomerase II (topo II) and convert the enzyme into an, inactive, salt-stable clamp around DNA. To better understand both topo II, and bisdioxopiperazine function, we determined the structures of the, adenosine 5'-[beta,gamma-imino]-triphosphate-bound yeast topo II ATPase, region (ScT2-ATPase) alone and complexed with the bisdioxopiperazine, ICRF-187. The drug-free form of the protein is similar in overall fold to, the equivalent region of bacterial gyrase but unexpectedly displays, significant conformational differences. The ternary drug-bound complex, reveals that ICRF-187 acts by an unusual mechanism of inhibition in which, the drug does not compete for the ATP-binding pocket, but bridges and, stabilizes a transient dimer interface between two ATPase protomers. Our, data explain why bisdioxopiperazines target ATP-bound topo II, provide a, structural rationale for the effects of certain drug-resistance mutations, and point to regions of bisdioxopiperazines that might be modified to, improve or alter drug specificity.
About this Structure
1QZR is a Single protein structure of sequence from Saccharomyces cerevisiae with MG, CDX and ANP as ligands. This structure superseeds the now removed PDB entry 1Q1D. Active as DNA topoisomerase (ATP-hydrolyzing), with EC number 5.99.1.3 Full crystallographic information is available from OCA.
Reference
Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187., Classen S, Olland S, Berger JM, Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10629-34. Epub 2003 Sep 8. PMID:12963818
Page seeded by OCA on Wed Nov 21 01:08:58 2007
