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Features of the Streptomyces hygroscopicus HtpG reveal how partial geldanamycin resistance can arise with mutation to the ATP binding pocket of a eukaryotic Hsp90
Author(s) -
Millson Stefan H.,
Chua ChunSong,
Roe S. Mark,
Polier Sigrun,
Solovieva Svetlana,
Pearl Laurence H.,
Sim TiowSuan,
Prodromou Chrisostomos,
Piper Peter W.
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-188821
Subject(s) - geldanamycin , streptomyces hygroscopicus , hsp90 , binding site , mutant , biochemistry , biology , chaperone (clinical) , chemistry , streptomyces , genetics , heat shock protein , medicine , bacteria , gene , pathology
Much attention is focused on the benzo‐quinone ansamycins as anticancer agents, with several derivatives of the natural product geldanamycin (GdA) now in clinical trials. These drugs are selective inhibitors of Hsp90, a molecular chaperone vital for many of the activities that drive cancer progression. Mutational changes to their interaction site, the extremely conserved ATP binding site of Hsp90, would mostly be predicted to inactivate the chaperone. As a result, drug resistance should not arise readily this way. Nevertheless, Streptomyces hygroscopicus , the actinomycete that produces GdA, has evolved an Hsp90 family protein (HtpG) that lacks GdA binding. It is altered in certain of the highly conserved amino acids making contacts to this antibiotic in crystal structures of GdA bound to eukaryotic forms of Hsp90. Two of these amino acid changes, located on one side of the nucleotide‐binding cleft, weakened GdA/Hsp90 binding and conferred partial GdA resistance when inserted into the endogenous Hsp90 of yeast cells. Crystal structures revealed their main effect to be a weakening of interactions with the C‐12 methoxy group of the GdA ansamycin ring. This is the first study to demonstrate that partial GdA resistance is possible by mutation within the ATP binding pocket of Hsp90.—Millson, S. H., Chua, C.‐S., Roe, S. M., Polier, S., Solovieva, S., Pearl, L. H., Sim, T.‐S., Prodromou, C., Piper, P. W. Features of the Streptomyces hygroscopicus HtpG reveal how partial geldanamycin resistance can arise with mutation to the ATP binding pocket of a eukaryotic Hsp90. FASEB J. 25, 3828–3837 (2011). www.fasebj.org