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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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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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Item Type: Article
Status: Published
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


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