1QZR

CRYSTAL STRUCTURE OF THE ATPASE REGION OF SACCHAROMYCES CEREVISIAE TOPOISOMERASE II BOUND TO ICRF-187 (DEXRAZOXANE)

Replaces:  1Q1D

Summary for 1QZR

• Entry DOI: 10.2210/pdb1qzr/pdb
• Related: 1BGW 1BJT 1PVG
• Descriptor: DNA topoisomerase II, MAGNESIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total)
• Functional Keywords: ghkl atpase domain, icrf, icrf-187, dexrazoxane, isomerase
• Biological source: Saccharomyces cerevisiae (baker's yeast)
• Cellular location: Nucleus: P06786
• Total number of polymer chains: 2
• Total formula weight: 97527.15

Authors

Classen, S.,Olland, S.,Berger, J.M. (deposition date: 2003-09-17, release date: 2003-09-30, Last modification date: 2023-08-23)

Primary citation

Classen, S.,Olland, S.,Berger, J.M.
Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187
Proc.Natl.Acad.Sci.USA, 100:10629-10634, 2003

PubMed Abstract: 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.

PubMed: 12963818
DOI: 10.1073/pnas.1832879100

Experimental method

X-RAY DIFFRACTION (1.9 Å)