Functional Analysis of Hsp70 Inhibitors

The molecular chaperones of the Hsp70 family have been recognized as targets for anti-cancer therapy. Since several paralogs of Hsp70 proteins exist in cytosol, endoplasmic reticulum and mitochondria, we investigated which isoform needs to be down-regulated for reducing viability of cancer cells. Fo...

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Main Authors:	Schlecht, Rainer, Scholz, Sebastian R., Dahmen, Heike, Wegener, Ansgar, Sirrenberg, Christian, Musil, Djordje, Bomke, Joerg, Eggenweiler, Hans-Michael, Mayer, Matthias P., Bukau, Bernd
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827032/

id	pubmed-3827032
recordtype	oai_dc
spelling	pubmed-38270322013-11-21 Functional Analysis of Hsp70 Inhibitors Schlecht, Rainer Scholz, Sebastian R. Dahmen, Heike Wegener, Ansgar Sirrenberg, Christian Musil, Djordje Bomke, Joerg Eggenweiler, Hans-Michael Mayer, Matthias P. Bukau, Bernd Research Article The molecular chaperones of the Hsp70 family have been recognized as targets for anti-cancer therapy. Since several paralogs of Hsp70 proteins exist in cytosol, endoplasmic reticulum and mitochondria, we investigated which isoform needs to be down-regulated for reducing viability of cancer cells. For two recently identified small molecule inhibitors, VER-155008 and 2-phenylethynesulfonamide (PES), which are proposed to target different sites in Hsp70s, we analyzed the molecular mode of action in vitro. We found that for significant reduction of viability of cancer cells simultaneous knockdown of heat-inducible Hsp70 (HSPA1) and constitutive Hsc70 (HSPA8) is necessary. The compound VER-155008, which binds to the nucleotide binding site of Hsp70, arrests the nucleotide binding domain (NBD) in a half-open conformation and thereby acts as ATP-competitive inhibitor that prevents allosteric control between NBD and substrate binding domain (SBD). Compound PES interacts with the SBD of Hsp70 in an unspecific, detergent-like fashion, under the conditions tested. None of the two inhibitors investigated was isoform-specific. Public Library of Science 2013-11-12 /pmc/articles/PMC3827032/ /pubmed/24265689 http://dx.doi.org/10.1371/journal.pone.0078443 Text en © 2013 Schlecht et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Schlecht, Rainer Scholz, Sebastian R. Dahmen, Heike Wegener, Ansgar Sirrenberg, Christian Musil, Djordje Bomke, Joerg Eggenweiler, Hans-Michael Mayer, Matthias P. Bukau, Bernd
spellingShingle	Schlecht, Rainer Scholz, Sebastian R. Dahmen, Heike Wegener, Ansgar Sirrenberg, Christian Musil, Djordje Bomke, Joerg Eggenweiler, Hans-Michael Mayer, Matthias P. Bukau, Bernd Functional Analysis of Hsp70 Inhibitors
author_facet	Schlecht, Rainer Scholz, Sebastian R. Dahmen, Heike Wegener, Ansgar Sirrenberg, Christian Musil, Djordje Bomke, Joerg Eggenweiler, Hans-Michael Mayer, Matthias P. Bukau, Bernd
author_sort	Schlecht, Rainer
title	Functional Analysis of Hsp70 Inhibitors
title_short	Functional Analysis of Hsp70 Inhibitors
title_full	Functional Analysis of Hsp70 Inhibitors
title_fullStr	Functional Analysis of Hsp70 Inhibitors
title_full_unstemmed	Functional Analysis of Hsp70 Inhibitors
title_sort	functional analysis of hsp70 inhibitors
description	The molecular chaperones of the Hsp70 family have been recognized as targets for anti-cancer therapy. Since several paralogs of Hsp70 proteins exist in cytosol, endoplasmic reticulum and mitochondria, we investigated which isoform needs to be down-regulated for reducing viability of cancer cells. For two recently identified small molecule inhibitors, VER-155008 and 2-phenylethynesulfonamide (PES), which are proposed to target different sites in Hsp70s, we analyzed the molecular mode of action in vitro. We found that for significant reduction of viability of cancer cells simultaneous knockdown of heat-inducible Hsp70 (HSPA1) and constitutive Hsc70 (HSPA8) is necessary. The compound VER-155008, which binds to the nucleotide binding site of Hsp70, arrests the nucleotide binding domain (NBD) in a half-open conformation and thereby acts as ATP-competitive inhibitor that prevents allosteric control between NBD and substrate binding domain (SBD). Compound PES interacts with the SBD of Hsp70 in an unspecific, detergent-like fashion, under the conditions tested. None of the two inhibitors investigated was isoform-specific.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827032/
_version_	1612026415405858816

Functional Analysis of Hsp70 Inhibitors

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