Cruentaren A Binds F1F0 ATP Synthase To Modulate the Hsp90 Protein Folding Machinery

• Published in: ACS chemical biology Vol. 9; no. 4; pp. 976 - 985
• Main Authors: Hall, Jessica A, Kusuma, Bhaskar Reddy, Brandt, Gary E. L, Blagg, Brian S. J
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 18.04.2014
• Subjects: Blotting, Western; Cell Line, Tumor; Dose-Response Relationship, Drug; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - chemistry; Humans; Inhibitory Concentration 50; Macrolides - metabolism; Macrolides - pharmacology; MCF-7 Cells; Mitochondrial Proton-Translocating ATPases - drug effects; Mitochondrial Proton-Translocating ATPases - metabolism; Molecular Structure; Protein Binding; Protein Folding
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/cb400906e

The molecular chaperone Hsp90 requires the assistance of immunophilins, co-chaperones, and partner proteins for the conformational maturation of client proteins. Hsp90 inhibition represents a promising anticancer strategy due to the dependence of numerous oncogenic signaling pathways upon Hsp90 function. Historically, small molecules have been designed to inhibit ATPase activity at the Hsp90 N-terminus; however, these molecules also induce the pro-survival heat shock response (HSR). Therefore, inhibitors that exhibit alternative mechanisms of action that do not elicit the HSR are actively sought. Small molecules that disrupt Hsp90-co-chaperone interactions can destabilize the Hsp90 complex without induction of the HSR, which leads to inhibition of cell proliferation. In this article, selective inhibition of F1F0 ATP synthase by cruentaren A was shown to disrupt the Hsp90-F1F0 ATP synthase interaction and result in client protein degradation without induction of the HSR.