Posttranslational modification and conformational state of Heat Shock Protein 90 differentially affect binding of chemically diverse small molecule inhibitors
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Kristin Beebe1, Mehdi Mollapour1,7,8, Bradley Scroggins1, Chrisostomos Prodromou2, Wanping Xu1, Mari Tokita1, Tony Taldone3, Lester Pullen4, Bettina K. Zierer5, Min-Jung Lee6, Jane Trepel6, Johannes Buchner5, Daniel Bolon4, Gabriela Chiosis3, Leonard Neckers1
1 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
2 University of Sussex, John Maynard Smith Building, Falmer, Brighton, UK
3 Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
4 University of Massachusetts Medical School, Department of Biochemistry and Molecular Pharmacology, Worcester, MA, USA
5 Technische Universität München, Department of Chemistry, Garching, Munich, Germany
6 Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
7 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA
8 Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA
Len Neckers, email:
Keywords: Hsp90, posttranslational modification, phosphorylation, drug binding, Hsp90 inhibitor
Received: June 14, 2013 Accepted: July 5, 2013 Published: July 7, 2013
Heat shock protein 90 (Hsp90) is an essential molecular chaperone in eukaryotes that facilitates the conformational maturation and function of a diverse protein clientele, including aberrant and/or over-expressed proteins that are involved in cancer growth and survival. A role for Hsp90 in supporting the protein homeostasis of cancer cells has buoyed interest in the utility of Hsp90 inhibitors as anti-cancer drugs. Despite the fact that all clinically evaluated Hsp90 inhibitors target an identical nucleotide-binding pocket in the N domain of the chaperone, the precise determinants that affect drug binding in the cellular environment remain unclear, and it is possible that chemically distinct inhibitors may not share similar binding preferences. Here we demonstrate that two chemically unrelated Hsp90 inhibitors, the benzoquinone ansamycin geldanamycin and the purine analog PU-H71, select for overlapping but not identical subpopulations of total cellular Hsp90, even though both inhibitors bind to an amino terminal nucleotide pocket and prevent N domain dimerization. Our data also suggest that PU-H71 is able to access a broader range of N domain undimerized Hsp90 conformations than is geldanamycin and is less affected by Hsp90 phosphorylation, consistent with its broader and more potent anti-tumor activity. A more complete understanding of the impact of the cellular milieu on small molecule inhibitor binding to Hsp90 should facilitate their more effective use in the clinic.
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