Molecular insights into the interaction of Hsp90 with allosteric inhibitors targeting the C-terminal domain

MedChemComm
Vasantha Kumar MvIoannis Gelis

Abstract

Unique to targeting the C-terminal domain of Hsp90 (C-Hsp90) is the ability to uncouple the cytotoxic and cytoprotective outcomes of Hsp90 modulation. After the identification of novobiocin as a C-Hsp90 interacting ligand a diverse gamut of novologues emerged, from which KU-32 and KU-596 exhibited strong neuroprotective activity. However, further development of these ligands is hampered by the difficulty to obtain structural information on their complexes with Hsp90. Using saturation transfer difference (STD) NMR spectroscopy, we found that the primary binding epitopes of KU-32 and KU596 map at the ring systems of the ligands and specifically the coumarin and biphenyl structures, respectively. Based on both relative and absolute STD effects, we identified KU-596 sites that can be explored to design novel third-generation novologues. In addition, chemical shift perturbations obtained by methyl-TROSY reveal that novologues bind at the cryptic, C-Hsp90 ATP-binding pocket and produce global, long-range structural rearrangements to dimeric Hsp90.

References

Aug 30, 1994·Proceedings of the National Academy of Sciences of the United States of America·L WhitesellL M Neckers
Feb 3, 2000·Journal of the National Cancer Institute·M G MarcuL Neckers
Jan 24, 2002·The Journal of Biological Chemistry·Cyrille GarnierVincent Peyrot
Aug 1, 2002·Proceedings of the National Academy of Sciences of the United States of America·Nancy M Bonini
Jan 11, 2003·Proceedings of the National Academy of Sciences of the United States of America·Fei DouHuaxi Xu
Mar 27, 2004·The Journal of Biological Chemistry·Jochen KluckenPamela J McLean
Apr 1, 2004·Journal of the American Chemical Society·Moriz Mayer, Thomas L James
Apr 21, 2006·Nature·Maruf M U AliLaurence H Pearl
May 22, 2007·Annals of the New York Academy of Sciences·Paul WorkmanNeal Rosen
Feb 16, 2008·Science·William E BalchJeffery W Kelly
Jan 14, 2009·Bioorganic & Medicinal Chemistry·Yuanming LuBrian S J Blagg
Dec 25, 2010·Proceedings of the National Academy of Sciences of the United States of America·G Elif KaragözStefan G D Rüdiger
Jun 11, 2011·Journal of Molecular Biology·Sung Jean ParkH Jane Dyson
Jul 22, 2011·Nature·F Ulrich HartlManajit Hayer-Hartl
Sep 29, 2011·Nature Chemical Biology·Kamalika MoulickGabriela Chiosis
Sep 29, 2011·European Biophysics Journal : EBJ·Jesus Angulo, Pedro M Nieto
Jan 5, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Len Neckers, Paul Workman
Nov 23, 2013·The Journal of Pharmacology and Experimental Therapeutics·Jiacheng MaRick T Dobrowsky
Mar 4, 2014·Cell·G Elif KaragözStefan G D Rüdiger
May 9, 2014·Science·Tomohide SaioCharalampos G Kalodimos
Oct 9, 2014·Annual Review of Pharmacology and Toxicology·William B PrattAndrew P Lieberman
Mar 19, 2015·Annual Review of Biochemistry·Johnathan Labbadia, Richard I Morimoto
Mar 19, 2016·Biopolymers·Laurence H Pearl
Feb 17, 2017·Chemistry : a European Journal·Ilda D'AnnessaGiorgio Colombo
Feb 22, 2017·Nature Structural & Molecular Biology·Javier OrozMarkus Zweckstetter
Apr 22, 2017·Nature Reviews. Molecular Cell Biology·Florian H SchopfJohannes Buchner
Sep 16, 2017·International Journal of Molecular Sciences·Suman Chatterjee, Timothy F Burns
Dec 6, 2017·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Abbey D ZuehlkeLen Neckers
Apr 21, 2018·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Sonja SchmidThorsten Hugel

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Methods Mentioned

BETA
NMR
column chromatography

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