Cruentaren A binds F1F0 ATP synthase to modulate the Hsp90 protein folding machinery.
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.
Department of Medicinal Chemistry, The University of Kansas , 1251 Wescoe Hall Drive, Malott 4070, Lawrence, Kansas 66045-7562, United States.
Jessica A
JA
Hall
Bhaskar Reddy
BR
Kusuma
Gary E L
GE
Brandt
Brian S J
BS
Blagg
D015153:Blotting, Western; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D018942:Macrolides / Q000378:metabolism* / Q000494:pharmacology; D025261:Mitochondrial Proton-Translocating ATPases / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D011485:Protein Binding; D017510:Protein Folding
D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; C516694:cruentaren A; C474451:F1F0-ATP synthase; D025261:Mitochondrial Proton-Translocating ATPases