1pvg
From Proteopedia
(New page: 200px<br /><applet load="1pvg" size="450" color="white" frame="true" align="right" spinBox="true" caption="1pvg, resolution 1.80Å" /> '''Crystal Structure of...) |
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| - | [[Image:1pvg.gif|left|200px]]<br /><applet load="1pvg" size=" | + | [[Image:1pvg.gif|left|200px]]<br /><applet load="1pvg" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1pvg, resolution 1.80Å" /> | caption="1pvg, resolution 1.80Å" /> | ||
'''Crystal Structure of the ATPase region of Saccharomyces Cerevisiae topoisomerase II'''<br /> | '''Crystal Structure of the ATPase region of Saccharomyces Cerevisiae topoisomerase II'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Type IIA topoisomerases both manage the topological state of chromosomal | + | 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== | ==About this Structure== | ||
| - | 1PVG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] with MG and ANP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/DNA_topoisomerase_(ATP-hydrolyzing) DNA topoisomerase (ATP-hydrolyzing)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.3 5.99.1.3] Full crystallographic information is available from [http:// | + | 1PVG is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Saccharomyces_cerevisiae Saccharomyces cerevisiae] with <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=ANP:'>ANP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/DNA_topoisomerase_(ATP-hydrolyzing) DNA topoisomerase (ATP-hydrolyzing)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.99.1.3 5.99.1.3] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1PVG OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Saccharomyces cerevisiae]] | [[Category: Saccharomyces cerevisiae]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Berger, J | + | [[Category: Berger, J M.]] |
[[Category: Classen, S.]] | [[Category: Classen, S.]] | ||
[[Category: Olland, S.]] | [[Category: Olland, S.]] | ||
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[[Category: ghkl atpase domain]] | [[Category: ghkl atpase domain]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:33:00 2008'' |
Revision as of 12:33, 21 February 2008
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Crystal Structure of the ATPase region of Saccharomyces Cerevisiae topoisomerase II
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
1PVG is a Single protein structure of sequence from Saccharomyces cerevisiae with and as ligands. 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
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