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Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity

Fewell, SW and Smith, CM and Lyon, MA and Dumitrescu, TP and Wipf, P and Day, BW and Brodsky, JL (2004) Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity. Journal of Biological Chemistry, 279 (49). 51131 - 51140. ISSN 0021-9258

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Abstract

The molecular chaperone and cytoprotective activities of the Hsp70 and Hsp40 chaperones represent therapeutic targets for human diseases such as cancer and those that arise from defects in protein folding; however, very few Hsp70 and no Hsp40 modulators have been described. Using an assay for ATP hydrolysis, we identified and screened small molecules with structural similarity to 15-deoxyspergualin and NSC 630668-R/1 for their effects on endogenous and Hsp40-stimulated Hsp70 ATPase activity. Several of these compounds modulated Hsp70 ATPase activity, consistent with the action of NSC 630668-R/1 observed previously (Fewell, S. W., Day, B. W., and Brodsky, J. L. (2001) J. Biol. Chem. 276, 910-914). In contrast, three compounds inhibited the ability of Hsp40 to stimulate Hsp70 ATPase activity but did not affect the endogenous activity of Hsp70. Two of these agents also compromised the Hsp70/Hsp40-mediated post-translational translocation of a secreted pre-protein in vitro. Together, these data indicate the potential for continued screening of small molecule Hsp70 effectors and that specific modulators of Hsp70-Hsp40 interaction can be obtained, potentially for future therapeutic use.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Fewell, SW
Smith, CM
Lyon, MA
Dumitrescu, TP
Wipf, Ppwipf@pitt.eduPWIPF
Day, BW
Brodsky, JLjbrodsky@pitt.eduJBRODSKY0000-0002-6984-8486
Date: 3 December 2004
Date Type: Publication
Journal or Publication Title: Journal of Biological Chemistry
Volume: 279
Number: 49
Page Range: 51131 - 51140
DOI or Unique Handle: 10.1074/jbc.m404857200
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0021-9258
MeSH Headings: Adenosine Triphosphatases--chemistry; Adenosine Triphosphate--chemistry; Antibiotics, Antineoplastic--pharmacology; Biological Transport; Dose-Response Relationship, Drug; Guanidines--pharmacology; HSP40 Heat-Shock Proteins; HSP70 Heat-Shock Proteins--chemistry; HSP70 Heat-Shock Proteins--physiology; Heat-Shock Proteins--chemistry; Humans; Hydrolysis; Models, Chemical; Models, Molecular; Molecular Chaperones--chemistry; Protein Binding; Protein Conformation; Protein Processing, Post-Translational; Protein Transport; Software; Structure-Activity Relationship; Thermodynamics; Time Factors
PubMed ID: 15448148
Date Deposited: 30 Jan 2014 17:03
Last Modified: 02 Feb 2019 16:56
URI: http://d-scholarship.pitt.edu/id/eprint/20393

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