Stimulation of heat shock protein 90 chaperone function through binding of a novobiocin analog KU-32

The Journal of Biological Chemistry
Bhaskar K ChatterjeeTapan K Chaudhuri

Abstract

Heat shock protein 90 (Hsp90) is a eukaryotic chaperone responsible for the folding and functional activation of numerous client proteins, many of which are oncoproteins. Thus, Hsp90 inhibition has been intensely pursued, resulting in the development of many potential Hsp90 inhibitors, not all of which are well-characterized. Hsp90 inhibitors not only abrogate its chaperone functions, but also could help us gain insight into the structure-function relationship of this chaperone. Here, using biochemical and cell-based assays along with isothermal titration calorimetry, we investigate KU-32, a derivative of the Hsp90 inhibitor novobiocin (NB), for its ability to modulate Hsp90 chaperone function. Although NB and KU-32 differ only slightly in structure, we found that upon binding, they induce completely opposite conformational changes in Hsp90. We observed that NB and KU-32 both bind to the C-terminal domain of Hsp90, but surprisingly, KU-32 stimulated the chaperone functions of Hsp90 via allosteric modulation of its N-terminal domain, responsible for the chaperone's ATPase activity. In vitro and in silico studies indicated that upon KU-32 binding, Hsp90 undergoes global structural changes leading to the formation of a "partially ...Continue Reading

References

Jan 6, 1999·Proceedings of the National Academy of Sciences of the United States of America·Y XuS Lindquist
Feb 3, 2000·Journal of the National Cancer Institute·M G MarcuL Neckers
Jul 7, 2001·The Journal of Biological Chemistry·K RichterJ Buchner
Dec 26, 2001·The Journal of Biological Chemistry·Barbara A L OwenDavid O Toft
Feb 4, 2003·Experimental Biology and Medicine·William B Pratt, David O Toft
Sep 11, 2004·The Journal of Biological Chemistry·Lin MüllerJohannes Buchner
Oct 7, 2004·Cancer Biology & Therapy·Leticia B A RangelPatrice J Morin
Jan 12, 2005·Nature Structural & Molecular Biology·Wanping XuLen Neckers
Sep 15, 2005·Journal of the American Chemical Society·Xiao Ming YuBrian S J Blagg
Dec 24, 2005·Proceedings of the National Academy of Sciences of the United States of America·Michal SafranWilliam G Kaelin
Feb 8, 2006·The Journal of Biological Chemistry·Klaus RichterJohannes Buchner
Feb 6, 2007·Bioorganic & Medicinal Chemistry Letters·Sabah AnsarBrian S J Blagg
Feb 14, 2008·Journal of Cell Science·Gregor P LotzWolfgang M J Obermann
May 22, 2008·The Journal of Biological Chemistry·Christian N CunninghamDavid A Agard
May 31, 2008·Proceedings of the National Academy of Sciences of the United States of America·Giorgio ColomboGennady Verkhivker
Nov 11, 2008·Current Medicinal Chemistry·Alison Donnelly, Brian S J Blagg
Oct 30, 2009·Nature·N R TanvirC Wolf
Jun 10, 2010·Nature Reviews. Molecular Cell Biology·Mikko TaipaleSusan Lindquist
May 10, 2011·ACS Chemical Biology·Robert L MattsBrian S J Blagg
Dec 14, 2011·Biochimica Et Biophysica Acta·Tatiana DidenkoStefan G D Rüdiger
Feb 10, 2012·Acta Biochimica Et Biophysica Sinica·Jian LiJianhua He
Apr 7, 2012·Communicative & Integrative Biology·Samuel M LeeLian Li
Sep 7, 2012·Neoplasia : an International Journal for Oncology Research·Aarif AhsanMukesh K Nyati
Nov 8, 2012·Experimental Diabetes Research·Soo Jin YangCheol-Young Park
Jan 15, 2013·ACS Medicinal Chemistry Letters·Huiping ZhaoBrian S J Blagg
Jan 30, 2013·Proceedings of the National Academy of Sciences of the United States of America·Jarrod B FrenchStephen J Benkovic
Aug 21, 2013·Journal of Molecular Biology·Soumya DaturpalliSophie E Jackson
Feb 6, 2014·Journal of the Peripheral Nervous System : JPNS·Anne VitalClaude Vital
Sep 10, 2014·Current Protocols in Bioinformatics·Benjamin Webb, Andrej Sali
Oct 9, 2014·Annual Review of Pharmacology and Toxicology·William B PrattAndrew P Lieberman
Nov 12, 2014·BioMed Research International·Panchanan MaitiSally Frautschy
Dec 17, 2014·International Journal of Oncology·Zuzana SolárováPeter Solár
Apr 14, 2015·Scientific Reports·Huaqun ZhangNaixia Zhang

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