Novobiocin and Related Coumarins and Depletion of Heat Shock Protein 90-Dependent Signaling Proteins

Marcu, Monica G.; Schulte, Theodore W.; Neckers, Leonard Μ.

doi:10.1093/jnci/92.3.242

Cited by 382 publications

(377 citation statements)

References 31 publications

Supporting

Mentioning

360

Contrasting

Unclassified

Order By: Relevance

“…Novobiocin is a small molecule inhibitor that binds to the CTD of Hsp90 (Marcu et al, 2000a;Marcu et al, 2000b;Soti et al, 2002). Like GA and radicicol, novobiocin inhibits the formation of Hsp90 complexes with client or p23, but unlike GA it also reduces the affinity of Hsp90 for TPR-containing co-chaperones that bind to the CTD (Allan et al, 2006;Yun et al, 2004).…”

Section: Small Molecules Also Shift the Conformation Of Hsp90mentioning

confidence: 99%

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

282

262

View full text Add to dashboard Cite

The molecular chaperone Hsp90 is an essential eukaryotic protein that makes up 1-2% of all cytosolic proteins. Hsp90 is vital for the maturation and maintenance of a wide variety of substrate proteins largely involved in signaling and regulatory processes. Many of these substrates have also been implicated in cancer and other diseases making Hsp90 an attractive target for therapeutics. Hsp90 is a highly dynamic and flexible molecule that can adapt its conformation to the wide variety of substrate proteins with which it acts. Large conformational rearrangements are also required for the activation of these client proteins. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis shifts the equilibrium between a pre-existing set of conformational states in an organismdependent manner. In vivo Hsp90 functions as part of larger heterocomplexes. The binding partners of Hsp90, co-chaperones, assist in the recruitment and activation of substrates, and many co-chaperones further regulate the conformational dynamics of Hsp90 by shifting the conformational equilibrium towards a particular state. Studies have also suggested alternative mechanisms for the regulation of Hsp90's conformation. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90 and the role that nucleotide, co-chaperones, post-translational modification and clients play in regulating Hsp90's conformation. We also discuss the effects of current Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.

show abstract

Section: Small Molecules Also Shift the Conformation Of Hsp90mentioning

confidence: 99%

Conformational dynamics of the molecular chaperone Hsp90

Krukenberg

Street

Lavery

et al. 2011

Quart. Rev. Biophys.

282

262

View full text Add to dashboard Cite

show abstract

“…6c). Half-maximal inhibition of binding occurs with Ϸ100 M NB and 1 M CP, comparable to their apoptotic potencies (36,37).…”

Section: Resultsmentioning

confidence: 85%

“…However, CP and NB bind to the C terminus of HSP90 both in vitro and in vivo (35)(36)(37). CP binds HSP90, decreasing the transcriptional activity of androgen and glucocorticoid receptors although not affecting other HSPregulated proteins, such as the phosphokinases Raf-1, Lck, and c-Src (37).…”

Section: Discussionmentioning

confidence: 99%

“…CP binds HSP90, decreasing the transcriptional activity of androgen and glucocorticoid receptors although not affecting other HSPregulated proteins, such as the phosphokinases Raf-1, Lck, and c-Src (37). NB binding to HSP90 can allosterically interfere with the binding to its N terminus of proteins such as mutant p53 and Raf-1 (36). Our findings indicate that CP and NB exert their cytotoxic effects, at least in part, by disrupting IP6K2-HSP90 binding, leading to augmented IP7(5) formation.…”

Section: Discussionmentioning

confidence: 99%

“…and C-terminal-[CP, novobiocin (NB), etc.] binding compounds inhibit its chaperone activity and client-protein interaction (29)(30)(31)(32)(33)(34)(35)(36).…”

mentioning

confidence: 99%

See 2 more Smart Citations

HSP90 regulates cell survival via inositol hexakisphosphate kinase-2

Chakraborty

Koldobskiy

Sixt

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

108

119

View full text Add to dashboard Cite

Heat-shock proteins (HSPs) are abundant, inducible proteins best known for their ability to maintain the conformation of proteins and to refold damaged proteins. Some HSPs, especially HSP90, can be antiapoptotic and the targets of anticancer drugs. Inositol hexakisphosphate kinase-2 (IP6K2), one of a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], mediates apoptosis. Increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. We now show that HSP90 physiologically binds IP6K2 and inhibits its catalytic activity. Drugs and selective mutations that abolish HSP90 -IP6K2 binding elicit activation of IP6K2, leading to cell death. Thus, the prosurvival actions of HSP90 reflect the inhibition of IP6K2, suggesting that selectively blocking this interaction could provide effective and safer modes of chemotherapy.apoptosis ͉ cisplatin ͉ novobiocin ͉ inositol polyphosphate

show abstract

Hsp 90 Inhibitors

Blagg

Hadden

2010

Burger's Medicinal Chemistry and Drug Discovery

View full text Add to dashboard Cite

The Hsp90 molecular chaperones represent a promising target for the development of anticancer and neuroprotective agents as they are responsible for the conformational maturation of numerous signaling proteins and the refolding of aggregated proteins, respectively. In this chapter, a summary of recent developments toward the treatment of these diseases by small‐molecule modulators of Hsp90 is provided.

show abstract

Novobiocin and Related Coumarins and Depletion of Heat Shock Protein 90-Dependent Signaling Proteins

Cited by 382 publications

References 31 publications

Conformational dynamics of the molecular chaperone Hsp90

Conformational dynamics of the molecular chaperone Hsp90

HSP90 regulates cell survival via inositol hexakisphosphate kinase-2

Hsp 90 Inhibitors

Contact Info

Product

Resources

About