2hkj
From Proteopedia
(New page: 200px<br /><applet load="2hkj" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hkj, resolution 2.00Å" /> '''Topoisomerase VI-B b...) |
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| - | [[Image:2hkj.gif|left|200px]]<br /><applet load="2hkj" size=" | + | [[Image:2hkj.gif|left|200px]]<br /><applet load="2hkj" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2hkj, resolution 2.00Å" /> | caption="2hkj, resolution 2.00Å" /> | ||
'''Topoisomerase VI-B bound to radicicol'''<br /> | '''Topoisomerase VI-B bound to radicicol'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Members of the GHL ATPase superfamily, including type II topoisomerases, Hsp90-class chaperones, and MutL, all share a common GHKL-type ATP-binding | + | Members of the GHL ATPase superfamily, including type II topoisomerases, Hsp90-class chaperones, and MutL, all share a common GHKL-type ATP-binding fold and act as nucleotide-controlled 'molecular clamps'. These enzymes' ATP-binding sites have proven to be rich drug targets, and certain inhibitors of type II topoisomerases and Hsp90 bind to this region and competitively inhibit these enzymes. Recently, it was found that radicicol, a drug known to block Hsp90 function, also inhibits the archaeal type IIB topoisomerase topo VI. Here, we use X-ray crystallography to show that despite low sequence identity ( approximately 10-12%) between topo VI and Hsp90, radicicol binds to the ATPase sites of these two enzymes in an equivalent manner. We further demonstrate that radicicol inhibits both the dimerization of the topo VI ATPase domains and ATP hydrolysis, two critical steps in the enzyme's strand passage reaction. This work contributes to a growing set of structures detailing the interactions between GHL-family proteins and various drugs, and reveals radicicol as a versatile scaffold for targeting distantly related GHL enzymes. |
==About this Structure== | ==About this Structure== | ||
| - | 2HKJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sulfolobus_shibatae Sulfolobus shibatae] with MG, DMS and RDC 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:// | + | 2HKJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Sulfolobus_shibatae Sulfolobus shibatae] with <scene name='pdbligand=MG:'>MG</scene>, <scene name='pdbligand=DMS:'>DMS</scene> and <scene name='pdbligand=RDC:'>RDC</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=2HKJ OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Sulfolobus shibatae]] | [[Category: Sulfolobus shibatae]] | ||
| - | [[Category: Berger, J | + | [[Category: Berger, J M.]] |
| - | [[Category: Corbett, K | + | [[Category: Corbett, K D.]] |
[[Category: DMS]] | [[Category: DMS]] | ||
[[Category: MG]] | [[Category: MG]] | ||
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[[Category: topoisomerase]] | [[Category: topoisomerase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:42:50 2008'' |
Revision as of 15:42, 21 February 2008
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Topoisomerase VI-B bound to radicicol
Overview
Members of the GHL ATPase superfamily, including type II topoisomerases, Hsp90-class chaperones, and MutL, all share a common GHKL-type ATP-binding fold and act as nucleotide-controlled 'molecular clamps'. These enzymes' ATP-binding sites have proven to be rich drug targets, and certain inhibitors of type II topoisomerases and Hsp90 bind to this region and competitively inhibit these enzymes. Recently, it was found that radicicol, a drug known to block Hsp90 function, also inhibits the archaeal type IIB topoisomerase topo VI. Here, we use X-ray crystallography to show that despite low sequence identity ( approximately 10-12%) between topo VI and Hsp90, radicicol binds to the ATPase sites of these two enzymes in an equivalent manner. We further demonstrate that radicicol inhibits both the dimerization of the topo VI ATPase domains and ATP hydrolysis, two critical steps in the enzyme's strand passage reaction. This work contributes to a growing set of structures detailing the interactions between GHL-family proteins and various drugs, and reveals radicicol as a versatile scaffold for targeting distantly related GHL enzymes.
About this Structure
2HKJ is a Single protein structure of sequence from Sulfolobus shibatae 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
Structural basis for topoisomerase VI inhibition by the anti-Hsp90 drug radicicol., Corbett KD, Berger JM, Nucleic Acids Res. 2006;34(15):4269-77. Epub 2006 Aug 18. PMID:16920739
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