Nucleic Acids Research Advance Access originally published online on August 18, 2006
Nucleic Acids Research 2006 34(15):4269-4277; doi:10.1093/nar/gkl567
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Nucleic Acids Research, 2006, Vol. 34, No. 15 4269-4277
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Nucleic Acid Enzymes |
Structural basis for topoisomerase VI inhibition by the anti-Hsp90 drug radicicol
Department of Molecular and Cellular Biology, 237 Hildebrand Hall #3206, University of California, Berkeley Berkeley, CA 94720-3206, USA
*To whom correspondence should be addressed. Tel: +1 510 643 9483; Fax: +1 510 643 9290; Email: jmberger{at}berkeley.edu
Received June 22, 2006. Revised July 21, 2006. Accepted July 21, 2006.
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 (
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.