1qzr
From Proteopedia
|
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 , and as ligands. This structure supersedes 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 Thu Feb 21 14:45:27 2008
