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• W2094311654 endingPage "e110115" @default.
• W2094311654 startingPage "e110115" @default.
• W2094311654 abstract "Hsp104 is a hexameric AAA+ protein that utilizes energy from ATP hydrolysis to dissolve disordered protein aggregates as well as amyloid fibers. Interestingly, Hsp104 orthologues are found in all kingdoms of life except animals. Thus, Hsp104 could represent an interesting drug target. Specific inhibition of Hsp104 activity might antagonize non-metazoan parasites that depend on a potent heat shock response, while producing little or no side effects to the host. However, no small molecule inhibitors of Hsp104 are known except guanidinium chloride. Here, we screen over 16,000 small molecules and identify 16 novel inhibitors of Hsp104 ATPase activity. Excluding compounds that inhibited Hsp104 activity by non-specific colloidal effects, we defined Suramin as an inhibitor of Hsp104 ATPase activity. Suramin is a polysulphonated naphthylurea and is used as an antiprotozoal drug for African Trypanosomiasis. Suramin also interfered with Hsp104 disaggregase, unfoldase, and translocase activities, and the inhibitory effect of Suramin was not rescued by Hsp70 and Hsp40. Suramin does not disrupt Hsp104 hexamers and does not effectively inhibit ClpB, the E. coli homolog of Hsp104, establishing yet another key difference between Hsp104 and ClpB behavior. Intriguingly, a potentiated Hsp104 variant, Hsp104A503V, is more sensitive to Suramin than wild-type Hsp104. By contrast, Hsp104 variants bearing inactivating sensor-1 mutations in nucleotide-binding domain (NBD) 1 or 2 are more resistant to Suramin. Thus, Suramin depends upon ATPase events at both NBDs to exert its maximal effect. Suramin could develop into an important mechanistic probe to study Hsp104 structure and function." @default.
• W2094311654 created "2016-06-24" @default.
• W2094311654 creator A5029295305 @default.
• W2094311654 creator A5072155842 @default.
• W2094311654 creator A5084836766 @default.
• W2094311654 date "2014-10-09" @default.
• W2094311654 modified "2023-10-16" @default.
• W2094311654 title "Suramin Inhibits Hsp104 ATPase and Disaggregase Activity" @default.
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• W2094311654 doi "https://doi.org/10.1371/journal.pone.0110115" @default.
• W2094311654 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4192545" @default.
• W2094311654 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25299406" @default.
• W2094311654 hasPublicationYear "2014" @default.
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