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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Autores principales: Rainer Schlecht, Sebastian R Scholz, Heike Dahmen, Ansgar Wegener, Christian Sirrenberg, Djordje Musil, Joerg Bomke, Hans-Michael Eggenweiler, Matthias P Mayer, Bernd Bukau
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Publicado: Public Library of Science (PLoS) 2013
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Acceso en línea:https://doaj.org/article/61d0e4e74a9e4efa87d2fb910f1f8022
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spelling oai:doaj.org-article:61d0e4e74a9e4efa87d2fb910f1f80222021-11-18T08:47:09ZFunctional analysis of Hsp70 inhibitors.1932-620310.1371/journal.pone.0078443https://doaj.org/article/61d0e4e74a9e4efa87d2fb910f1f80222013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24265689/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Rainer SchlechtSebastian R ScholzHeike DahmenAnsgar WegenerChristian SirrenbergDjordje MusilJoerg BomkeHans-Michael EggenweilerMatthias P MayerBernd BukauPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e78443 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Rainer Schlecht
Sebastian R Scholz
Heike Dahmen
Ansgar Wegener
Christian Sirrenberg
Djordje Musil
Joerg Bomke
Hans-Michael Eggenweiler
Matthias P Mayer
Bernd Bukau
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.
format article
author Rainer Schlecht
Sebastian R Scholz
Heike Dahmen
Ansgar Wegener
Christian Sirrenberg
Djordje Musil
Joerg Bomke
Hans-Michael Eggenweiler
Matthias P Mayer
Bernd Bukau
author_facet Rainer Schlecht
Sebastian R Scholz
Heike Dahmen
Ansgar Wegener
Christian Sirrenberg
Djordje Musil
Joerg Bomke
Hans-Michael Eggenweiler
Matthias P Mayer
Bernd Bukau
author_sort Rainer Schlecht
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.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/61d0e4e74a9e4efa87d2fb910f1f8022
work_keys_str_mv AT rainerschlecht functionalanalysisofhsp70inhibitors
AT sebastianrscholz functionalanalysisofhsp70inhibitors
AT heikedahmen functionalanalysisofhsp70inhibitors
AT ansgarwegener functionalanalysisofhsp70inhibitors
AT christiansirrenberg functionalanalysisofhsp70inhibitors
AT djordjemusil functionalanalysisofhsp70inhibitors
AT joergbomke functionalanalysisofhsp70inhibitors
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