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• W659487895 endingPage "1485" @default.
• W659487895 startingPage "1476" @default.
• W659487895 abstract "Cyclophilins are peptidyl cis-trans prolyl isomerases (PPIases), whose activity is typically inhibited by cyclosporine A (CsA), a potent immunosuppressor. Cyclophilins are also chaperones. Emerging evidence supports that cyclophilins present nonoverlapping PPIase and chaperone activities. The proteostasis of the disease-relevant substrates, signal transducer and activator of transcription 3 and 5 (STAT3/STAT5), heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), and M-opsin, is regulated by nonoverlapping chaperone and PPIase activities of the cyclophilin domain (CY) of Ranbp2, a multifunctional and modular scaffold that controls nucleocytoplasmic shuttling and proteostasis of selective substrates. Although highly homologous, CY and the archetypal cyclophilin A (CyPA) present distinct catalytic and CsA-binding activities owing to unique structural features between these cylophilins. We explored structural idiosyncrasies between CY and CyPA to screen in silico nearly 9 million small molecules (SM) against the CY PPIase pocket and identify SMs with selective bioactivity toward STAT3, hnRNPA2B1, or M-opsin proteostasis. We found three classes of SMs that enhance the cytokine-stimulated transcriptional activity of STAT3 without changing latent and activated STAT3 levels, down-regulate hnRNPA2B1 or M-opsin proteostasis, or a combination of these. Further, a SM that suppresses hnRNPA2B1 proteostasis also inhibits strongly and selectively the PPIase activity of CY. This study unravels chemical probes for multimodal regulation of CY of Ranbp2 and its substrates, and this regulation likely results in the allosterism stemming from the interconversion of conformational substates of cyclophilins. The results also demonstrate the feasibility of CY in drug discovery against disease-relevant substrates controlled by Ranbp2, and they open new opportunities for therapeutic interventions." @default.
• W659487895 created "2016-06-24" @default.
• W659487895 creator A5003667568 @default.
• W659487895 creator A5044972049 @default.
• W659487895 creator A5077192224 @default.
• W659487895 creator A5082248052 @default.
• W659487895 date "2015-06-12" @default.
• W659487895 modified "2023-10-16" @default.
• W659487895 title "Targeting the Cyclophilin Domain of Ran-binding Protein 2 (Ranbp2) with Novel Small Molecules to Control the Proteostasis of STAT3, hnRNPA2B1 and M-Opsin" @default.
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• W659487895 doi "https://doi.org/10.1021/acschemneuro.5b00134" @default.
• W659487895 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4556350" @default.
• W659487895 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26030368" @default.

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