Structural basis for topoisomerase VI inhibition by the anti-Hsp90 drug radicicol.
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.
Corbett
Kevin D
KD
Department of Molecular and Cellular Biology, 237 Hildebrand Hall #3206, University of California, Berkeley, Berkeley, CA 94720-3206, USA.
Berger
James M
JM
D000251:Adenosine Triphosphatases / Q000378:metabolism; D019843:Archaeal Proteins; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000187:drug effects; D018942:Macrolides / Q000494:pharmacology*; D011487:Protein Conformation
D019843:Archaeal Proteins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; D000251:Adenosine Triphosphatases; C105141:DNA topoisomerase VI; D004250:DNA Topoisomerases, Type II; C035359:monorden